Inter-Src homology 2 (iSH2) helical domain of Class IA Phosphoinositide 3-kinase Regulatory subunit 3, PIK3R3, also called p55gamma; PI3Ks catalyze the transfer of the gamma-phosphoryl group from ATP to the 3-hydroxyl of the inositol ring of D-myo-phosphatidylinositol (PtdIns) or its derivatives. They play an important role in a variety of fundamental cellular processes, including cell motility, the Ras pathway, vesicle trafficking and secretion, immune cell activation, and apoptosis. They are classified according to their substrate specificity, regulation, and domain structure. Class IA PI3Ks are heterodimers of a p110 catalytic (C) subunit and a p85-related regulatory (R) subunit. The R subunit down-regulates PI3K basal activity, stabilizes the C subunit, and plays a role in the activation downstream of tyrosine kinases. All R subunits contain two SH2 domains that flank an intervening helical domain (iSH2), which binds to the N-terminal adaptor-binding domain (ABD) of the catalytic subunit. p55gamma, also called PIK3R3 or p55PIK, also contains a unique N-terminal 24-amino acid residue (N24) that interacts with cell cycle modulators to promote cell cycle progression.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 742641593 189 DNIDAVGKKLQEYHSQYQEKSKEYDRLYEEYTRTSQEIQMKRTAIEAFNETIKIFEEQCHTQEQHSKEYIERFRREGNEK 268
Cdd:cd12925    1 DNIDAVGRKLQEYHSQYQEKSKEYDRLYEEYTKTSQEIQMKRTAIEAFNETIKIFEEQCHTQERYSKEYIERFRREGNEK 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 742641593 269 EIERIMMNYDKLKSRLGEIHDSKMRLEQDLKNQALDNREIDKKMNSIKPDLIQLRKIRDQHLVWLNHKGVRQKRLNVWLG 348
Cdd:cd12925   81 EIERIMMNYEKLKSRLGEIHDSKMRLEQDLKTQALDNREIDKKMNSIKPDLIQLRKIRDQYLVWLNHKGVRQKRINDWLG 160

                 .
gi 742641593 349 I 349
Cdd:cd12925  161 I 161

C-terminal Src homology 2 (cSH2) domain found in p85; Phosphoinositide 3-kinases (PI3Ks) are essential for cell growth, migration, and survival. p110, the catalytic subunit, is composed of an adaptor-binding domain, a Ras-binding domain, a C2 domain, a helical domain, and a kinase domain. The regulatory unit is called p85 and is composed of an SH3 domain, a RhoGap domain, a N-terminal SH2 (nSH2) domain, a inter SH2 (iSH2) domain, and C-terminal (cSH2) domain. There are 2 inhibitory interactions between p110alpha and p85 of P13K: 1) p85 nSH2 domain with the C2, helical, and kinase domains of p110alpha and 2) p85 iSH2 domain with C2 domain of p110alpha. There are 3 inhibitory interactions between p110beta and p85 of P13K: 1) p85 nSH2 domain with the C2, helical, and kinase domains of p110beta, 2) p85 iSH2 domain with C2 domain of p110alpha, and 3) p85 cSH2 domain with the kinase domain of p110alpha. It is interesting to note that p110beta is oncogenic as a wild type protein while p110alpha lacks this ability. One explanation is the idea that the regulation of p110beta by p85 is unique because of the addition of inhibitory contacts from the cSH2 domain and the loss of contacts in the iSH2 domain. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 742641593 368 PHYDEKTWFVEDINRVQAEDLLYGKPDGAFLIRESSKKGCYACSVVADGEVKHCVIYSTARGYGFAEPYNLYSSLKELVL 447
Cdd:cd09930    1 PHHDERTWLVGDINRTQAEELLRGKPDGTFLIRESSTQGCYACSVVCNGEVKHCVIYKTETGYGFAEPYNLYESLKELVL 80

                         90       100
                 ....*....|....*....|....
gi 742641593 448 HYQQTSLVQHNDSLNVRLAYPVHA 471
Cdd:cd09930   81 HYAHNSLEQHNDSLTVTLAYPVLA 104

Inter-Src homology 2 (iSH2) helical domain of Class IA Phosphoinositide 3-kinase Regulatory subunit 3, PIK3R3, also called p55gamma; PI3Ks catalyze the transfer of the gamma-phosphoryl group from ATP to the 3-hydroxyl of the inositol ring of D-myo-phosphatidylinositol (PtdIns) or its derivatives. They play an important role in a variety of fundamental cellular processes, including cell motility, the Ras pathway, vesicle trafficking and secretion, immune cell activation, and apoptosis. They are classified according to their substrate specificity, regulation, and domain structure. Class IA PI3Ks are heterodimers of a p110 catalytic (C) subunit and a p85-related regulatory (R) subunit. The R subunit down-regulates PI3K basal activity, stabilizes the C subunit, and plays a role in the activation downstream of tyrosine kinases. All R subunits contain two SH2 domains that flank an intervening helical domain (iSH2), which binds to the N-terminal adaptor-binding domain (ABD) of the catalytic subunit. p55gamma, also called PIK3R3 or p55PIK, also contains a unique N-terminal 24-amino acid residue (N24) that interacts with cell cycle modulators to promote cell cycle progression.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 742641593 189 DNIDAVGKKLQEYHSQYQEKSKEYDRLYEEYTRTSQEIQMKRTAIEAFNETIKIFEEQCHTQEQHSKEYIERFRREGNEK 268
Cdd:cd12925    1 DNIDAVGRKLQEYHSQYQEKSKEYDRLYEEYTKTSQEIQMKRTAIEAFNETIKIFEEQCHTQERYSKEYIERFRREGNEK 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 742641593 269 EIERIMMNYDKLKSRLGEIHDSKMRLEQDLKNQALDNREIDKKMNSIKPDLIQLRKIRDQHLVWLNHKGVRQKRLNVWLG 348
Cdd:cd12925   81 EIERIMMNYEKLKSRLGEIHDSKMRLEQDLKTQALDNREIDKKMNSIKPDLIQLRKIRDQYLVWLNHKGVRQKRINDWLG 160

                 .
gi 742641593 349 I 349
Cdd:cd12925  161 I 161

N-terminal Src homology 2 (nSH2) domain found in p85; Phosphoinositide 3-kinases (PI3Ks) are essential for cell growth, migration, and survival. p110, the catalytic subunit, is composed of an adaptor-binding domain, a Ras-binding domain, a C2 domain, a helical domain, and a kinase domain. The regulatory unit is called p85 and is composed of an SH3 domain, a RhoGap domain, a N-terminal SH2 (nSH2) domain, an internal SH2 (iSH2) domain, and C-terminal (cSH2) domain. There are 2 inhibitory interactions between p110alpha and p85 of P13K: (1) p85 nSH2 domain with the C2, helical, and kinase domains of p110alpha and (2) p85 iSH2 domain with C2 domain of p110alpha. There are 3 inhibitory interactions between p110beta and p85 of P13K: (1) p85 nSH2 domain with the C2, helical, and kinase domains of p110beta, (2) p85 iSH2 domain with C2 domain of p110alpha, and (3) p85 cSH2 domain with the kinase domain of p110alpha. It is interesting to note that p110beta is oncogenic as a wild type protein while p110alpha lacks this ability. One explanation is the idea that the regulation of p110beta by p85 is unique because of the addition of inhibitory contacts from the cSH2 domain and the loss of contacts in the iSH2 domain. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 742641593  76 SLQDAEWYWGDISREEVNDKLRDMPDGTFLVRDASTkMQGDYTLTLRKGGNNKLIKIYHRDGKYGFSDPLTFNSVVELIN 155
Cdd:cd09942    3 SLQEAEWYWGDISREEVNEKMRDTPDGTFLVRDAST-MKGDYTLTLRKGGNNKLIKIFHRDGKYGFSDPLTFNSVVELIN 81

                         90       100
                 ....*....|....*....|....*....
gi 742641593 156 HYHHESLAQYNPKLDVKLMYPVSRYQQDQ 184
Cdd:cd09942   82 YYRNNSLAEYNRKLDVKLLYPVSRFQQDQ 110

Src homology 2 domains; Src homology 2 domains bind phosphotyrosine-containing polypeptides via 2 surface pockets. Specificity is provided via interaction with residues that are distinct from the phosphotyrosine. Only a single occurrence of a SH2 domain has been found in S. cerevisiae.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 742641593    81 EWYWGDISREEVNDKLRDMPDGTFLVRDaSTKMQGDYTLTLRKGGNNKLIKIYH-RDGKYGFSDPLTFNSVVELINHYHH 159
Cdd:smart00252   2 PWYHGFISREEAEKLLKNEGDGDFLVRD-SESSPGDYVLSVRVKGKVKHYRIRRnEDGKFYLEGGRKFPSLVELVEHYQK 80

                   ...
gi 742641593   160 ESL 162
Cdd:smart00252  81 NSL 83

SH2 domain;

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 742641593   82 WYWGDISREEVNDKLR-DMPDGTFLVRDASTKmQGDYTLTLRKGGNNKLIKI-YHRDGKYGFSDPLTFNSVVELINHY 157
Cdd:pfam00017   1 WYHGKISRQEAERLLLnGKPDGTFLVRESEST-PGGYTLSVRDDGKVKHYKIqSTDNGGYYISGGVKFSSLAELVEHY 77

chromosome segregation protein SMC, common bacterial type; SMC (structural maintenance of chromosomes) proteins bind DNA and act in organizing and segregating chromosomes for partition. SMC proteins are found in bacteria, archaea, and eukaryotes. This family represents the SMC protein of most bacteria. The smc gene is often associated with scpB (TIGR00281) and scpA genes, where scp stands for segregation and condensation protein. SMC was shown (in Caulobacter crescentus) to be induced early in S phase but present and bound to DNA throughout the cell cycle. [Cellular processes, Cell division, DNA metabolism, Chromosome-associated proteins]

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 742641593   158 HHESLAQYNPKLDvklmypvsRYQQDQLVKEDNIDAVGKKLQEYHSQYQEKSKEYDRLYEEYTRTSQEIQMKRTAIEAFN 237
Cdd:TIGR02168  237 LREELEELQEELK--------EAEEELEELTAELQELEEKLEELRLEVSELEEEIEELQKELYALANEISRLEQQKQILR 308

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 742641593   238 E-------TIKIFEEQCHTQEQHSKEYIERFRRegNEKEIERIMMNYDKLKSRLgeihDSKMRLEQDLKNQaldNREIDK 310
Cdd:TIGR02168  309 ErlanlerQLEELEAQLEELESKLDELAEELAE--LEEKLEELKEELESLEAEL----EELEAELEELESR---LEELEE 379

                          170
                   ....*....|....
gi 742641593   311 KMNSIKPDLIQLRK 324
Cdd:TIGR02168  380 QLETLRSKVAQLEL 393

Uncharacterized protein, contains DUF3084 domain [Function unknown];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 742641593 181 QQDQLVKEDN-IDAVGKKLQEYHSQYQEKSKEYDRLYEEYTRTSQEIQMKRTAIEAFNETIKIFEEQCHTQEQHSKEYIE 259
Cdd:COG4372   64 LEEELEQARSeLEQLEEELEELNEQLQAAQAELAQAQEELESLQEEAEELQEELEELQKERQDLEQQRKQLEAQIAELQS 143

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 742641593 260 RFRREgnEKEIERIMMNYDKLKSRLGEIHDSKMRLEQDLKNQALDN--REIDKKMNSIKPDLIQLRKIRDQHLVWLNHKG 337
Cdd:COG4372  144 EIAER--EEELKELEEQLESLQEELAALEQELQALSEAEAEQALDEllKEANRNAEKEEELAEAEKLIESLPRELAEELL 221

                        170       180       190       200       210       220       230
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 742641593 338 VRQKRLNV--------WLGIKNEDADENYFINEEDENLPHYDEKTWFVEDINRVQAEDLLYGKPDGAFLIRESSKK 405
Cdd:COG4372  222 EAKDSLEAklglalsaLLDALELEEDKEELLEEVILKEIEELELAILVEKDTEEEELEIAALELEALEEAALELKL 297

Inter-Src homology 2 (iSH2) helical domain of Class IA Phosphoinositide 3-kinase Regulatory subunit 3, PIK3R3, also called p55gamma; PI3Ks catalyze the transfer of the gamma-phosphoryl group from ATP to the 3-hydroxyl of the inositol ring of D-myo-phosphatidylinositol (PtdIns) or its derivatives. They play an important role in a variety of fundamental cellular processes, including cell motility, the Ras pathway, vesicle trafficking and secretion, immune cell activation, and apoptosis. They are classified according to their substrate specificity, regulation, and domain structure. Class IA PI3Ks are heterodimers of a p110 catalytic (C) subunit and a p85-related regulatory (R) subunit. The R subunit down-regulates PI3K basal activity, stabilizes the C subunit, and plays a role in the activation downstream of tyrosine kinases. All R subunits contain two SH2 domains that flank an intervening helical domain (iSH2), which binds to the N-terminal adaptor-binding domain (ABD) of the catalytic subunit. p55gamma, also called PIK3R3 or p55PIK, also contains a unique N-terminal 24-amino acid residue (N24) that interacts with cell cycle modulators to promote cell cycle progression.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 742641593 189 DNIDAVGKKLQEYHSQYQEKSKEYDRLYEEYTRTSQEIQMKRTAIEAFNETIKIFEEQCHTQEQHSKEYIERFRREGNEK 268
Cdd:cd12925    1 DNIDAVGRKLQEYHSQYQEKSKEYDRLYEEYTKTSQEIQMKRTAIEAFNETIKIFEEQCHTQERYSKEYIERFRREGNEK 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 742641593 269 EIERIMMNYDKLKSRLGEIHDSKMRLEQDLKNQALDNREIDKKMNSIKPDLIQLRKIRDQHLVWLNHKGVRQKRLNVWLG 348
Cdd:cd12925   81 EIERIMMNYEKLKSRLGEIHDSKMRLEQDLKTQALDNREIDKKMNSIKPDLIQLRKIRDQYLVWLNHKGVRQKRINDWLG 160

                 .
gi 742641593 349 I 349
Cdd:cd12925  161 I 161

Inter-Src homology 2 (iSH2) helical domain of Class IA Phosphoinositide 3-kinase Regulatory subunit 1, PIK3R1, also called p85alpha; PI3Ks catalyze the transfer of the gamma-phosphoryl group from ATP to the 3-hydroxyl of the inositol ring of D-myo-phosphatidylinositol (PtdIns) or its derivatives. They play an important role in a variety of fundamental cellular processes, including cell motility, the Ras pathway, vesicle trafficking and secretion, immune cell activation and apoptosis. They are classified according to their substrate specificity, regulation, and domain structure. Class IA PI3Ks are heterodimers of a p110 catalytic (C) subunit and a p85-related regulatory (R) subunit. The R subunit down-regulates PI3K basal activity, stabilizes the C subunit, and plays a role in the activation downstream of tyrosine kinases. All R subunits contain two SH2 domains that flank an intervening helical domain (iSH2), which binds to the N-terminal adaptor-binding domain (ABD) of the catalytic subunit. In addition, p85alpha, also called PIK3R1, contains N-terminal SH3 and GAP domains. p85alpha carry functions independent of its PI3K regulatory role. It can independently stimulate signaling pathways involved in cytoskeletal rearrangements. Insulin-sensitive tissues express splice variants of the PIK3R1 gene, p50alpha and p55alpha, which may play important roles in insulin signaling during lipid and glucose metabolism. Mice deficient with PIK3R1 die perinatally, indicating its importance in development.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 742641593 189 DNIDAVGKKLQEYHSQYQEKSKEYDRLYEEYTRTSQEIQMKRTAIEAFNETIKIFEEQCHTQEQHSKEYIERFRREGNEK 268
Cdd:cd12924    1 DNIEAVGKKLHEYNTQFQEKSREYDRLYEEYTRTSQEIQMKRTAIEAFNETIKIFEEQCQTQERYSKEYIEKFKREGNEK 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 742641593 269 EIERIMMNYDKLKSRLGEIHDSKMRLEQDLKNQALDNREIDKKMNSIKPDLIQLRKIRDQHLVWLNHKGVRQKRLNVWLG 348
Cdd:cd12924   81 EIQRIMHNYEKLKSRISEIVDSRRRLEEDLKKQAAEYREIDKRMNSIKPDLIQLRKTRDQYLMWLTQKGVRQKKLNEWLG 160

                 .
gi 742641593 349 I 349
Cdd:cd12924  161 N 161

N-terminal Src homology 2 (nSH2) domain found in p85; Phosphoinositide 3-kinases (PI3Ks) are essential for cell growth, migration, and survival. p110, the catalytic subunit, is composed of an adaptor-binding domain, a Ras-binding domain, a C2 domain, a helical domain, and a kinase domain. The regulatory unit is called p85 and is composed of an SH3 domain, a RhoGap domain, a N-terminal SH2 (nSH2) domain, an internal SH2 (iSH2) domain, and C-terminal (cSH2) domain. There are 2 inhibitory interactions between p110alpha and p85 of P13K: (1) p85 nSH2 domain with the C2, helical, and kinase domains of p110alpha and (2) p85 iSH2 domain with C2 domain of p110alpha. There are 3 inhibitory interactions between p110beta and p85 of P13K: (1) p85 nSH2 domain with the C2, helical, and kinase domains of p110beta, (2) p85 iSH2 domain with C2 domain of p110alpha, and (3) p85 cSH2 domain with the kinase domain of p110alpha. It is interesting to note that p110beta is oncogenic as a wild type protein while p110alpha lacks this ability. One explanation is the idea that the regulation of p110beta by p85 is unique because of the addition of inhibitory contacts from the cSH2 domain and the loss of contacts in the iSH2 domain. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 742641593  76 SLQDAEWYWGDISREEVNDKLRDMPDGTFLVRDASTkMQGDYTLTLRKGGNNKLIKIYHRDGKYGFSDPLTFNSVVELIN 155
Cdd:cd09942    3 SLQEAEWYWGDISREEVNEKMRDTPDGTFLVRDAST-MKGDYTLTLRKGGNNKLIKIFHRDGKYGFSDPLTFNSVVELIN 81

                         90       100
                 ....*....|....*....|....*....
gi 742641593 156 HYHHESLAQYNPKLDVKLMYPVSRYQQDQ 184
Cdd:cd09942   82 YYRNNSLAEYNRKLDVKLLYPVSRFQQDQ 110

Inter-Src homology 2 (iSH2) helical domain of Class IA Phosphoinositide 3-kinase Regulatory subunits; PI3Ks catalyze the transfer of the gamma-phosphoryl group from ATP to the 3-hydroxyl of the inositol ring of D-myo-phosphatidylinositol (PtdIns) or its derivatives. They play an important role in a variety of fundamental cellular processes, including cell motility, the Ras pathway, vesicle trafficking and secretion, immune cell activation, and apoptosis. They are classified according to their substrate specificity, regulation, and domain structure. Class IA PI3Ks are heterodimers of a p110 catalytic (C) subunit and a p85-related regulatory (R) subunit. The R subunit down-regulates PI3K basal activity, stabilizes the C subunit, and plays a role in the activation downstream of tyrosine kinases. All R subunits contain two SH2 domains that flank an intervening helical domain (iSH2), which binds to the N-terminal adaptor-binding domain (ABD) of the catalytic subunit. In vertebrates, there are three genes (PIK3R1, PIK3R2, and PIK3R3) that encode for different Class IA PI3K R subunits.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 742641593 189 DNIDAVGKKLQEYHSQYQEKSKEYDRLYEEYTRTSQEIQMKRTAIEAFNETIKIFEEQCHTQEQHSKEYierfrregNEK 268
Cdd:cd12923    1 DDVEKLAKKLKEINKEYLDKSREYDELYEKYNKLSQEIQLKRQALEAFEEAVKMFEEQLRTQEKFQKEA--------QPH 72

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 742641593 269 EIERIMMNYDKLKSRLGEIHDSKMRLEQDLKNQALDNREIDKKMNSIKPDLIQLRKIRDQHLVWLNHKGVRQKRLNVWLG 348
Cdd:cd12923   73 EKQRLMENNELLKSRLKELEESKEQLEEDLRKQVAYNRELEREMNSLKPELMQLRKQKDQYLRWLKRKGVSQEEINQLLK 152

SH2 domain;

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 742641593  375 WFVEDINRVQAEDLLY-GKPDGAFLIRES-SKKGCYACSVVADGEVKHCVIYSTARG--YGFAEPYnlYSSLKELVLHY 449
Cdd:pfam00017   1 WYHGKISRQEAERLLLnGKPDGTFLVRESeSTPGGYTLSVRDDGKVKHYKIQSTDNGgyYISGGVK--FSSLAELVEHY 77

Src homology 2 domains; Src homology 2 domains bind phosphotyrosine-containing polypeptides via 2 surface pockets. Specificity is provided via interaction with residues that are distinct from the phosphotyrosine. Only a single occurrence of a SH2 domain has been found in S. cerevisiae.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 742641593   375 WFVEDINRVQAEDLLYGKPDGAFLIRES-SKKGCYACSVVADGEVKHCVIYSTARGYGFAEPYNLYSSLKELVLHYQQTS 453
Cdd:smart00252   3 WYHGFISREEAEKLLKNEGDGDFLVRDSeSSPGDYVLSVRVKGKVKHYRIRRNEDGKFYLEGGRKFPSLVELVEHYQKNS 82

                   ..
gi 742641593   454 LV 455
Cdd:smart00252  83 LG 84

Src homology 2 (SH2) domain; In general, SH2 domains are involved in signal transduction; they bind pTyr-containing polypeptide ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites. They are present in a wide array of proteins including: adaptor proteins (Nck1, Crk, Grb2), scaffolds (Slp76, Shc, Dapp1), kinases (Src, Syk, Fps, Tec), phosphatases (Shp-1, Shp-2), transcription factors (STAT1), Ras signaling molecules (Ras-Gap), ubiquitination factors (c-Cbl), cytoskeleton regulators (Tensin), signal regulators (SAP), and phospholipid second messengers (PLCgamma), amongst others.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 742641593  81 EWYWGDISREEVNDKLRDMPDGTFLVRDaSTKMQGDYTLTLRKGGNN-KLIKIYHRDGKYGF--SDPLTFNSVVELINHY 157
Cdd:cd00173    1 PWFHGSISREEAERLLRGKPDGTFLVRE-SSSEPGDYVLSVRSGDGKvKHYLIERNEGGYYLlgGSGRTFPSLPELVEHY 79

N-terminal Src homology 2 (nSH2) domain found in p85; Phosphoinositide 3-kinases (PI3Ks) are essential for cell growth, migration, and survival. p110, the catalytic subunit, is composed of an adaptor-binding domain, a Ras-binding domain, a C2 domain, a helical domain, and a kinase domain. The regulatory unit is called p85 and is composed of an SH3 domain, a RhoGap domain, a N-terminal SH2 (nSH2) domain, an internal SH2 (iSH2) domain, and C-terminal (cSH2) domain. There are 2 inhibitory interactions between p110alpha and p85 of P13K: (1) p85 nSH2 domain with the C2, helical, and kinase domains of p110alpha and (2) p85 iSH2 domain with C2 domain of p110alpha. There are 3 inhibitory interactions between p110beta and p85 of P13K: (1) p85 nSH2 domain with the C2, helical, and kinase domains of p110beta, (2) p85 iSH2 domain with C2 domain of p110alpha, and (3) p85 cSH2 domain with the kinase domain of p110alpha. It is interesting to note that p110beta is oncogenic as a wild type protein while p110alpha lacks this ability. One explanation is the idea that the regulation of p110beta by p85 is unique because of the addition of inhibitory contacts from the cSH2 domain and the loss of contacts in the iSH2 domain. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 742641593 372 EKTWFVEDINRVQAEDLLYGKPDGAFLIRE-SSKKGCYACSVVADGEVKHCVIYSTARGYGFAEPYNlYSSLKELVLHYQ 450
Cdd:cd09942    6 EAEWYWGDISREEVNEKMRDTPDGTFLVRDaSTMKGDYTLTLRKGGNNKLIKIFHRDGKYGFSDPLT-FNSVVELINYYR 84

                         90
                 ....*....|....*....
gi 742641593 451 QTSLVQHNDSLNVRLAYPV 469
Cdd:cd09942   85 NNSLAEYNRKLDVKLLYPV 103

Src homology 2 (SH2) domain found in the Vav family; Vav proteins are involved in several processes that require cytoskeletal reorganization, such as the formation of the immunological synapse (IS), phagocytosis, platelet aggregation, spreading, and transformation. Vavs function as guanine nucleotide exchange factors (GEFs) for the Rho/Rac family of GTPases. Vav family members have several conserved motifs/domains including: a leucine-rich region, a leucine-zipper, a calponin homology (CH) domain, an acidic domain, a Dbl-homology (DH) domain, a pleckstrin homology (PH) domain, a cysteine-rich domain, 2 SH3 domains, a proline-rich region, and a SH2 domain. Vavs are the only known Rho GEFs that have both the DH/PH motifs and SH2/SH3 domains in the same protein. The leucine-rich helix-loop-helix (HLH) domain is thought to be involved in protein heterodimerization with other HLH proteins and it may function as a negative regulator by forming inactive heterodimers. The CH domain is usually involved in the association with filamentous actin, but in Vav it controls NFAT stimulation, Ca2+ mobilization, and its transforming activity. Acidic domains are involved in protein-protein interactions and contain regulatory tyrosines. The DH domain is a GDP-GTP exchange factor on Rho/Rac GTPases. The PH domain in involved in interactions with GTP-binding proteins, lipids and/or phosphorylated serine/threonine residues. The SH3 domain is involved in localization of proteins to specific sites within the cell interacting with protein with proline-rich sequences. The SH2 domain mediates a high affinity interaction with tyrosine phosphorylated proteins. There are three Vav mammalian family members: Vav1 which is expressed in the hematopoietic system, Vav2 and Vav3 are more ubiquitously expressed. The members here include insect and amphibian Vavs. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 742641593  81 EWYWGDISREEVNDKLRDMPDGTFLVRdASTKMQGDYTLTLRKGGNNKLIKIYHR-DGKYGFSDPLTFNSVVELINHYHH 159
Cdd:cd09940    6 LWFVGEMERDTAENRLENRPDGTYLVR-VRPQGETQYALSIKYNGDVKHMKIEQRsDGLYYLSESRHFKSLVELVNYYER 84

                         90
                 ....*....|....*...
gi 742641593 160 ESLAQYNPKLDVKLMYPV 177
Cdd:cd09940   85 NSLGENFAGLDTTLKWPY 102

C-terminal Src homology 2 (C-SH2) domain in Phospholipase C gamma; Phospholipase C gamma is a signaling molecule that is recruited to the C-terminal tail of the receptor upon autophosphorylation of a highly conserved tyrosine. PLCgamma is composed of a Pleckstrin homology (PH) domain followed by an elongation factor (EF) domain, 2 catalytic regions of PLC domains that flank 2 tandem SH2 domains (N-SH2, C-SH2), and ending with a SH3 domain and C2 domain. N-SH2 SH2 domain-mediated interactions represent a crucial step in transmembrane signaling by receptor tyrosine kinases. SH2 domains recognize phosphotyrosine (pY) in the context of particular sequence motifs in receptor phosphorylation sites. Both N-SH2 and C-SH2 have a very similar binding affinity to pY. But in growth factor stimulated cells these domains bind to different target proteins. N-SH2 binds to pY containing sites in the C-terminal tails of tyrosine kinases and other receptors. Recently it has been shown that this interaction is mediated by phosphorylation-independent interactions between a secondary binding site found exclusively on the N-SH2 domain and a region of the FGFR1 tyrosine kinase domain. This secondary site on the SH2 cooperates with the canonical pY site to regulate selectivity in mediating a specific cellular process. C-SH2 binds to an intramolecular site on PLCgamma itself which allows it to hydrolyze phosphatidylinositol-4,5-bisphosphate into diacylglycerol and inositol triphosphate. These then activate protein kinase C and release calcium. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 742641593 370 YDEKTWFVEDINRVQAEDLLYGKP-DGAFLIRESSK-KGCYACSVVADGEVKHCVIYSTARGY--GFAEpynlYSSLKEL 445
Cdd:cd09932    1 HESKEWFHANLTREQAEEMLMRVPrDGAFLVRPSETdPNSFAISFRAEGKIKHCRIKQEGRLFviGTSQ----FESLVEL 76

                         90       100
                 ....*....|....*....|....*...
gi 742641593 446 VLHYQQTSLVQhndslNVRLAYPVHAQM 473
Cdd:cd09932   77 VSYYEKHPLYR-----KIKLRYPVNEEL 99

Src homology 2 (SH2) domain found in suppressor of cytokine signaling (SOCS) proteins; SH2 domain found in SOCS proteins. SOCS was first recognized as a group of cytokine-inducible SH2 (CIS) domain proteins comprising eight family members in human (CIS and SOCS1-SOCS7). In addition to the SH2 domain, SOCS proteins have a variable N-terminal domain and a conserved SOCS box in the C-terminal domain. SOCS proteins bind to a substrate via their SH2 domain. The prototypical members, CIS and SOCS1-SOCS3, have been shown to regulate growth hormone signaling in vitro and in a classic negative feedback response compete for binding at phosphotyrosine sites in JAK kinase and receptor pathways to displace effector proteins and target bound receptors for proteasomal degradation. Loss of SOCS activity results in excessive cytokine signaling associated with a variety of hematopoietic, autoimmune, and inflammatory diseases and certain cancers. Members (SOCS4-SOCS7) were identified by their conserved SOCS box, an adapter motif of 3 helices that associates substrate binding domains, such as the SOCS SH2 domain, ankryin, and WD40 with ubiquitin ligase components. These show limited cytokine induction. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 742641593  82 WYWGDISREEVNDKLRDMPDGTFLVRDASTKMqgdYTLTL--RKGGNNKLIKIYHRDGKYGF---SDPLTFNSVVELINH 156
Cdd:cd10387   12 WYWGPITRWEAEGKLANVPDGSFLVRDSSDDR---YLLSLsfRSHGKTLHTRIEHSNGRFSFyeqPDVEGHTSIVDLIEH 88

Src homology 2 (SH2) domain found in Carboxyl-Terminal Src Kinase (Csk); Both the C-terminal Src kinase (CSK) and CSK-homologous kinase (CHK) are members of the CSK-family of protein tyrosine kinases. These proteins suppress activity of Src-family kinases (SFK) by selectively phosphorylating the conserved C-terminal tail regulatory tyrosine by a similar mechanism. CHK is also capable of inhibiting SFKs by a non-catalytic mechanism that involves binding of CHK to SFKs to form stable protein complexes. The unphosphorylated form of SFKs is inhibited by CSK and CHK by a two-step mechanism. The first step involves the formation of a complex of SFKs with CSK/CHK with the SFKs in the complex are inactive. The second step, involves the phosphorylation of the C-terminal tail tyrosine of SFKs, which then dissociates and adopt an inactive conformation. The structural basis of how the phosphorylated SFKs dissociate from CSK/CHK to adopt the inactive conformation is not known. The inactive conformation of SFKs is stabilized by two intramolecular inhibitory interactions: (a) the pYT:SH2 interaction in which the phosphorylated C-terminal tail tyrosine (YT) binds to the SH2 domain, and (b) the linker:SH3 interaction of which the SH2-kinase domain linker binds to the SH3 domain. SFKs are activated by multiple mechanisms including binding of the ligands to the SH2 and SH3 domains to displace the two inhibitory intramolecular interactions, autophosphorylation, and dephosphorylation of YT. By selective phosphorylation and the non-catalytic inhibitory mechanism CSK and CHK are able to inhibit the active forms of SFKs. CSK and CHK are regulated by phosphorylation and inter-domain interactions. They both contain SH3, SH2, and kinase domains separated by the SH3-SH2 connector and SH2 kinase linker, intervening segments separating the three domains. They lack a conserved tyrosine phosphorylation site in the kinase domain and the C-terminal tail regulatory tyrosine phosphorylation site. The CSK SH2 domain is crucial for stabilizing the kinase domain in the active conformation. A disulfide bond here regulates CSK kinase activity. The subcellular localization and activity of CSK are regulated by its SH2 domain. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 742641593  82 WYWGDISREEVNDKLRDMPDGTFLVRDaSTKMQGDYTLTLRKGGNNKLIKIYHRDGKYGFSDPLTFNSVVELINHYHHES 161
Cdd:cd09937    5 WFHGKISREEAERLLQPPEDGLFLVRE-STNYPGDYTLCVSFEGKVEHYRVIYRNGKLTIDEEEYFENLIQLVEHYTKDA 83

Src homology 2 (SH2) domain found in Tec-like proteins; The Tec protein tyrosine kinase is the founding member of a family that includes Btk, Itk, Bmx, and Txk. The members have a PH domain, a zinc-binding motif, a SH3 domain, a SH2 domain, and a protein kinase catalytic domain. Btk is involved in B-cell receptor signaling with mutations in Btk responsible for X-linked agammaglobulinemia (XLA) in humans and X-linked immunodeficiency (xid) in mice. Itk is involved in T-cell receptor signaling. Tec is expressed in both T and B cells, and is thought to function in activated and effector T lymphocytes to induce the expression of genes regulated by NFAT transcription factors. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 742641593  76 SLQDAEWYWGDISREEVNDKLRDM-PDGTFLVRDASTKmqGDYTLTL-RKGGNNKLIKIYH----RDGKYGFSDPLTFNS 149
Cdd:cd09934    2 NLEKYEWYVGDMSRQRAESLLKQEdKEGCFVVRNSSTK--GLYTVSLfTKVPGSPHVKHYHikqnARSEFYLAEKHCFET 79

                         90       100       110
                 ....*....|....*....|....*....|.
gi 742641593 150 VVELINhYHheslaQYNPK-LDVKLMYPVSR 179
Cdd:cd09934   80 IPELIN-YH-----QHNSGgLATRLKYPVCD 104

Src homology 2 (SH2) domain found in suppressor of cytokine signaling (SOCS) proteins; SH2 domain found in SOCS proteins. SOCS was first recognized as a group of cytokine-inducible SH2 (CIS) domain proteins comprising eight family members in human (CIS and SOCS1-SOCS7). In addition to the SH2 domain, SOCS proteins have a variable N-terminal domain and a conserved SOCS box in the C-terminal domain. SOCS proteins bind to a substrate via their SH2 domain. The prototypical members, CIS and SOCS1-SOCS3, have been shown to regulate growth hormone signaling in vitro and in a classic negative feedback response compete for binding at phosphotyrosine sites in JAK kinase and receptor pathways to displace effector proteins and target bound receptors for proteasomal degradation. Loss of SOCS activity results in excessive cytokine signaling associated with a variety of hematopoietic, autoimmune, and inflammatory diseases and certain cancers. Members (SOCS4-SOCS7) were identified by their conserved SOCS box, an adapter motif of 3 helices that associates substrate binding domains, such as the SOCS SH2 domain, ankryin, and WD40 with ubiquitin ligase components. These show limited cytokine induction. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 742641593  71 KDSSVSLQDAEWYWGDISREEVNDKLRDMPDGTFLVRDASTKMqgdYTLTLRKGGNNKL--IKIYHRDGKYGFSDPLTF- 147
Cdd:cd10388    1 TASLRELKDCGWYWGPMSWEDAEKVLSNKPDGSFLVRDSSDDR---YIFSLSFRSQGSVhhTRIEQYQGTFSLGSRNKFv 77

                         90
                 ....*....|
gi 742641593 148 ---NSVVELI 154
Cdd:cd10388   78 drsQSLVEFI 87

Src homology 2 (SH2) domain found in the Vav3 proteins; Proto-oncogene vav is a member of the Dbl family of guanine nucleotide exchange factors (GEF) for the Rho family of GTP binding proteins. All vavs are activated by tyrosine phosphorylation leading to their activation. There are three Vav mammalian family members: Vav1 which is expressed in the hematopoietic system, and Vav2 and Vav3 are more ubiquitously expressed. Vav3 preferentially activates RhoA, RhoG and, to a lesser extent, Rac1. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. VAV3 has been shown to interact with Grb2. Vav proteins are involved in several processes that require cytoskeletal reorganization, such as the formation of the immunological synapse (IS), phagocytosis, platelet aggregation, spreading, and transformation. Vavs function as guanine nucleotide exchange factors (GEFs) for the Rho/Rac family of GTPases. Vav family members have several conserved motifs/domains including: a leucine-rich region, a leucine-zipper, a calponin homology (CH) domain, an acidic domain, a Dbl-homology (DH) domain, a pleckstrin homology (PH) domain, a cysteine-rich domain, 2 SH3 domains, a proline-rich region, and a SH2 domain. Vavs are the only known Rho GEFs that have both the DH/PH motifs and SH2/SH3 domains in the same protein. The leucine-rich helix-loop-helix (HLH) domain is thought to be involved in protein heterodimerization with other HLH proteins and it may function as a negative regulator by forming inactive heterodimers. The CH domain is usually involved in the association with filamentous actin, but in Vav it controls NFAT stimulation, Ca2+ mobilization, and its transforming activity. Acidic domains are involved in protein-protein interactions and contain regulatory tyrosines. The DH domain is a GDP-GTP exchange factor on Rho/Rac GTPases. The PH domain in involved in interactions with GTP-binding proteins, lipids and/or phosphorylated serine/threonine residues. The SH3 domain is involved in localization of proteins to specific sites within the cell interacting with protein with proline-rich sequences. The SH2 domain mediates a high affinity interaction with tyrosine phosphorylated proteins. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 742641593  82 WYWGDISREEVNDKLRDMPDGTFLVRDaSTKMQGDYTLTLRKGGNNKLIKIYHRDGKYGFSDPLTFNSVVELINHYHHES 161
Cdd:cd10407    7 WYAGAMERLQAETELINRVNSTYLVRH-RTKESGEYAISIKYNNEVKHIKILTRDGFFHIAENRKFKSLMELVEYYKHHS 85

                         90
                 ....*....|....*
gi 742641593 162 LAQYNPKLDVKLMYP 176
Cdd:cd10407   86 LKEGFRSLDTTLQFP 100

Src homology 2 (SH2) domain found in the Src family of non-receptor tyrosine kinases; The Src family kinases are nonreceptor tyrosine kinases that have been implicated in pathways regulating proliferation, angiogenesis, invasion and metastasis, and bone metabolism. It is thought that transforming ability of Src is linked to its ability to activate key signaling molecules in these pathways, rather than through direct activity. As such blocking Src activation has been a target for drug companies. Src family members can be divided into 3 groups based on their expression pattern: 1) Src, Fyn, and Yes; 2) Blk, Fgr, Hck, Lck, and Lyn; and 3) Frk-related kinases Frk/Rak and Iyk/Bsk Of these, cellular c-Src is the best studied and most frequently implicated in oncogenesis. The c-Src contains five distinct regions: a unique N-terminal domain, an SH3 domain, an SH2 domain, a kinase domain and a regulatory tail, as do the other members of the family. Src exists in both active and inactive conformations. Negative regulation occurs through phosphorylation of Tyr, resulting in an intramolecular association between phosphorylated Tyr and the SH2 domain of SRC, which locks the protein in a closed conformation. Further stabilization of the inactive state occurs through interactions between the SH3 domain and a proline-rich stretch of residues within the kinase domain. Conversely, dephosphorylation of Tyr allows SRC to assume an open conformation. Full activity requires additional autophosphorylation of a Tyr residue within the catalytic domain. Loss of the negative-regulatory C-terminal segment has been shown to result in increased activity and transforming potential. Phosphorylation of the C-terminal Tyr residue by C-terminal Src kinase (Csk) and Csk homology kinase results in increased intramolecular interactions and consequent Src inactivation. Specific phosphatases, protein tyrosine phosphatase a (PTPa) and the SH-containing phosphatases SHP1/SHP2, have also been shown to take a part in Src activation. Src is also activated by direct binding of focal adhesion kinase (Fak) and Crk-associated substrate (Cas) to the SH2 domain. SRC activity can also be regulated by numerous receptor tyrosine kinases (RTKs), such as Her2, epidermal growth factor receptor (EGFR), fibroblast growth factor receptor, platelet-derived growth factor receptor (PDGFR), and vascular endothelial growth factor receptor (VEGFR). In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 742641593  81 EWYWGDISREEVNDKL--RDMPDGTFLVRDASTKmQGDYTLTLR-----KGGNNKLIKIYHRD-GKYGFSDPLTFNSVVE 152
Cdd:cd09933    4 EWFFGKIKRKDAEKLLlaPGNPRGTFLIRESETT-PGAYSLSVRdgddaRGDTVKHYRIRKLDnGGYYITTRATFPTLQE 82

                 ....*
gi 742641593 153 LINHY 157
Cdd:cd09933   83 LVQHY 87

Src homology 2 (SH2) domain found in suppressor of cytokine signaling (SOCS) proteins; SH2 domain found in SOCS proteins. SOCS was first recognized as a group of cytokine-inducible SH2 (CIS) domain proteins comprising eight family members in human (CIS and SOCS1-SOCS7). In addition to the SH2 domain, SOCS proteins have a variable N-terminal domain and a conserved SOCS box in the C-terminal domain. SOCS proteins bind to a substrate via their SH2 domain. The prototypical members, CIS and SOCS1-SOCS3, have been shown to regulate growth hormone signaling in vitro and in a classic negative feedback response compete for binding at phosphotyrosine sites in JAK kinase and receptor pathways to displace effector proteins and target bound receptors for proteasomal degradation. Loss of SOCS activity results in excessive cytokine signaling associated with a variety of hematopoietic, autoimmune, and inflammatory diseases and certain cancers. Members (SOCS4-SOCS7) were identified by their conserved SOCS box, an adapter motif of 3 helices that associates substrate binding domains, such as the SOCS SH2 domain, ankryin, and WD40 with ubiquitin ligase components. These show limited cytokine induction. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 742641593  71 KDSSVSLQDAEWYWGDISREEVNDKLRDMPDGTFLVRDAStkmQGD--YTLTLRKGGNNKLIKIYHRDGKYGFSD-PLTF 147
Cdd:cd10382    1 TRTSAMLDASGFYWGPLSVEEAHAKLKREPVGTFLIRDSR---QKNcfFALSVKMASGPVSIRILFKAGKFSLDGsKESF 77

                         90
                 ....*....|
gi 742641593 148 NSVVELINHY 157
Cdd:cd10382   78 DCLFKLLEHY 87

Src homology 2 (SH2) domain found in HCK; HCK is a member of the Src non-receptor type tyrosine kinase family of proteins and is expressed in hemopoietic cells. HCK is proposed to couple the Fc receptor to the activation of the respiratory burst. It may also play a role in neutrophil migration and in the degranulation of neutrophils. It has two different translational starts that have different subcellular localization. HCK has been shown to interact with BCR gene, ELMO1 Cbl gene, RAS p21 protein activator 1, RASA3, Granulocyte colony-stimulating factor receptor, ADAM15 and RAPGEF1. Like the other members of the Src family the SH2 domain in addition to binding the target, also plays an autoinhibitory role by binding to its C-terminal tail. In general SH2 domains are involved in signal transduction. HCK has a unique N-terminal domain, an SH3 domain, an SH2 domain, a kinase domain and a regulatory tail, as do the other members of the family. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 742641593 375 WFVEDINRVQAEDLLY--GKPDGAFLIRES-SKKGCYACSV-----VADGEVKHCVIYSTARGYGFAEPYNLYSSLKELV 446
Cdd:cd10363    5 WFFKGISRKDAERQLLapGNMLGSFMIRDSeTTKGSYSLSVrdydpQHGDTVKHYKIRTLDNGGFYISPRSTFSTLQELV 84

                         90       100
                 ....*....|....*....|..
gi 742641593 447 LHYQQTSlvqhnDSLNVRLAYP 468
Cdd:cd10363   85 DHYKKGN-----DGLCQKLSVP 101

N-terminal Src homology 2 (N-SH2) domain in Phospholipase C gamma; Phospholipase C gamma is a signaling molecule that is recruited to the C-terminal tail of the receptor upon autophosphorylation of a highly conserved tyrosine. PLCgamma is composed of a Pleckstrin homology (PH) domain followed by an elongation factor (EF) domain, 2 catalytic regions of PLC domains that flank 2 tandem SH2 domains (N-SH2, C-SH2), and ending with a SH3 domain and C2 domain. N-SH2 SH2 domain-mediated interactions represent a crucial step in transmembrane signaling by receptor tyrosine kinases. SH2 domains recognize phosphotyrosine (pY) in the context of particular sequence motifs in receptor phosphorylation sites. Both N-SH2 and C-SH2 have a very similar binding affinity to pY. But in growth factor stimulated cells these domains bind to different target proteins. N-SH2 binds to pY containing sites in the C-terminal tails of tyrosine kinases and other receptors. Recently it has been shown that this interaction is mediated by phosphorylation-independent interactions between a secondary binding site found exclusively on the N-SH2 domain and a region of the FGFR1 tyrosine kinase domain. This secondary site on the SH2 cooperates with the canonical pY site to regulate selectivity in mediating a specific cellular process. C-SH2 binds to an intramolecular site on PLCgamma itself which allows it to hydrolyze phosphatidylinositol-4,5-bisphosphate into diacylglycerol and inositol triphosphate. These then activate protein kinase C and release calcium. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 742641593  81 EWYWGDIS--REEVNDKLRDM---PDGTFLVRDaSTKMQGDYTLTLRKGGNNKLIKIYHRDG----KYGFSDPLTFNSVV 151
Cdd:cd10341    5 PWFHGKLGdgRDEAEKLLLEYcegGDGTFLVRE-SETFVGDYTLSFWRNGKVQHCRIRSRQEngekKYYLTDNLVFDSLY 83

                         90
                 ....*....|.
gi 742641593 152 ELINHYHHESL 162
Cdd:cd10341   84 ELIDYYRQNPL 94

Src homology 2 domain found in dual adaptor for phosphotyrosine and 3-phosphoinositides ( DAPP1)/B lymphocyte adaptor molecule of 32 kDa (Bam32)-like proteins; DAPP1/Bam32 contains a putative myristoylation site at its N-terminus, followed by a SH2 domain, and a pleckstrin homology (PH) domain at its C-terminus. DAPP1 could potentially be recruited to the cell membrane by any of these domains. Its putative myristoylation site could facilitate the interaction of DAPP1 with the lipid bilayer. Its SH2 domain may also interact with phosphotyrosine residues on membrane-associated proteins such as activated tyrosine kinase receptors. And finally its PH domain exhibits a high-affinity interaction with the PtdIns(3,4,5)P(3) PtdIns(3,4)P(2) second messengers produced at the cell membrane following the activation of PI 3-kinases. DAPP1 is thought to interact with both tyrosine phosphorylated proteins and 3-phosphoinositides and therefore may play a role in regulating the location and/or activity of such proteins(s) in response to agonists that elevate PtdIns(3,4,5)P(3) and PtdIns(3,4)P(2). This protein is likely to play an important role in triggering signal transduction pathways that lie downstream from receptor tyrosine kinases and PI 3-kinase. It is likely that DAPP1 functions as an adaptor to recruit other proteins to the plasma membrane in response to extracellular signals. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 742641593 375 WFVEDINRVQAED-LLYGKPDGAFLIRESSKK-GCYACSVVADGEVKHcvIYSTARGYGFAEPYNLYSSLKELVLHY 449
Cdd:cd10355    8 WYHGNLTRHAAEAlLLSNGVDGSYLLRNSNEGtGLFSLSVRAKDSVKH--FHVEYTGYSFKFGFNEFSSLQDFVKHF 82

Src homology 2 (SH2) domain found in feline sarcoma, Fujinami poultry sarcoma, and fes-related (Fes/Fps/Fer) proteins; The Fps family consists of members Fps/Fes and Fer/Flk/Tyk3. They are cytoplasmic protein-tyrosine kinases implicated in signaling downstream from cytokines, growth factors and immune receptors. Fes/Fps/Fer contains three coiled-coil regions, an SH2 (Src-homology-2) and a TK (tyrosine kinase catalytic) domain signature. Members here include: Fps/Fes, Fer, Kin-31, and In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 742641593  76 SLQDAEWYWGDISREEVNDKLRDmpDGTFLVRDASTK--MQGDYTLTLRKGGNNKLIKIYHRDGKYGFSDPLTFNSVVEL 153
Cdd:cd10361    2 DLENEPYYHGLLPREDAEELLKN--DGDFLVRKTEPKggGKRKLVLSVRWDGKIRHFVINRDDGGKYYIEGKSFKSISEL 79

                 ....*
gi 742641593 154 INHYH 158
Cdd:cd10361   80 INYYQ 84

C-terminal Src homology 2 (C-SH2) domain found in SH2 domain Phosphatases (SHP) proteins; The SH2 domain phosphatases (SHP-1, SHP-2/Syp, Drosophila corkscrew (csw), and Caenorhabditis elegans Protein Tyrosine Phosphatase (Ptp-2)) are cytoplasmic signaling enzymes. They are both targeted and regulated by interactions of their SH2 domains with phosphotyrosine docking sites. These proteins contain two SH2 domains (N-SH2, C-SH2) followed by a tyrosine phosphatase (PTP) domain, and a C-terminal extension. Shp1 and Shp2 have two tyrosyl phosphorylation sites in their C-tails, which are phosphorylated differentially by receptor and nonreceptor PTKs. Csw retains the proximal tyrosine and Ptp-2 lacks both sites. Shp-binding proteins include receptors, scaffolding adapters, and inhibitory receptors. Some of these bind both Shp1 and Shp2 while others bind only one. Most proteins that bind a Shp SH2 domain contain one or more immuno-receptor tyrosine-based inhibitory motifs (ITIMs): [SIVL]xpYxx[IVL]. Shp1 N-SH2 domain blocks the catalytic domain and keeps the enzyme in the inactive conformation, and is thus believed to regulate the phosphatase activity of SHP-1. Its C-SH2 domain is thought to be involved in searching for phosphotyrosine activators. The SHP2 N-SH2 domain is a conformational switch; it either binds and inhibits the phosphatase, or it binds phosphoproteins and activates the enzyme. The C-SH2 domain contributes binding energy and specificity, but it does not have a direct role in activation. Csw SH2 domain function is essential, but either SH2 domain can fulfill this requirement. The role of the csw SH2 domains during Sevenless receptor tyrosine kinase (SEV) signaling is to bind Daughter of Sevenless rather than activated SEV. Ptp-2 acts in oocytes downstream of sheath/oocyte gap junctions to promote major sperm protein (MSP)-induced MAP Kinase (MPK-1) phosphorylation. Ptp-2 functions in the oocyte cytoplasm, not at the cell surface to inhibit multiple RasGAPs, resulting in sustained Ras activation. It is thought that MSP triggers PTP-2/Ras activation and ROS production to stimulate MPK-1 activity essential for oocyte maturation and that secreted MSP domains and Cu/Zn superoxide dismutases function antagonistically to control ROS and MAPK signaling. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

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gi 742641593  82 WYWGDISREEVNDKLRDMP-DGTFLVRDASTKmQGDYTLTLRKGgNNKL--IKIYHRDGKYGFSDPLTFNSVVELINHYh 158
Cdd:cd09931    2 WFHGHLSGKEAEKLLLEKGkPGSFLVRESQSK-PGDFVLSVRTD-DDKVthIMIRCQGGKYDVGGGEEFDSLTDLVEHY- 78

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gi 742641593 159 heslaQYNPKLD-----VKLMYPV 177
Cdd:cd09931   79 -----KKNPMVEtsgtvVHLKQPL 97