Protein Kinases, catalytic domain; The protein kinase superfamily is mainly composed of the catalytic domains of serine/threonine-specific and tyrosine-specific protein kinases. It also includes RIO kinases, which are atypical serine protein kinases, aminoglycoside phosphotransferases, and choline kinases. These proteins catalyze the transfer of the gamma-phosphoryl group from ATP to hydroxyl groups in specific substrates such as serine, threonine, or tyrosine residues of proteins.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217311970 388 NWRRGKLLGQGAFGRVYLCYDVDTGRELASKQVQFDPDSPETSKEVSALECEIQLLKNLQHERIVQYYGCLRDraEKTLT 467
Cdd:cd06625     1 NWKQGKLLGQGAFGQVYLCYDADTGRELAVKQVEIDPINTEASKEVKALECEIQLLKNLQHERIVQYYGCLQD--EKSLS 78

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|...
gi 2217311970 468 IFMEYMPGGSVKDQLKAYGALTESVTRKYTRQILEGMSYLHSNMIVHRDIKGA 520
Cdd:cd06625    79 IFMEYMPGGSVKDEIKAYGALTENVTRKYTRQILEGLAYLHSNMIVHRDIKGA 131

Catalytic domain of Mitogen-Activated Protein (MAP)/Extracellular signal-Regulated Kinase (ERK) Kinase Kinase 3-like Serine/Threonine Kinases; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. This subfamily is composed of MEKK3, MEKK2, and related proteins; all contain an N-terminal PB1 domain, which mediates oligomerization, and a C-terminal catalytic domain. MEKK2 and MEKK3 are MAPK kinase kinases (MAPKKKs or MKKK) that activate MEK5 (also called MKK5), which activates ERK5. The ERK5 cascade plays roles in promoting cell proliferation, differentiation, neuronal survival, and neuroprotection. MEKK3 plays an essential role in embryonic angiogenesis and early heart development. MEKK2 and MEKK3 can also activate the MAPKs, c-Jun N-terminal kinase (JNK) and p38, through their respective MAPKKs. The MEKK3-like subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217311970 388 NWRRGKLLGQGAFGRVYLCYDVDTGRELASKQVQFDPDSPETSKEVSALECEIQLLKNLQHERIVQYYGCLRDraEKTLT 467
Cdd:cd06625     1 NWKQGKLLGQGAFGQVYLCYDADTGRELAVKQVEIDPINTEASKEVKALECEIQLLKNLQHERIVQYYGCLQD--EKSLS 78

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|...
gi 2217311970 468 IFMEYMPGGSVKDQLKAYGALTESVTRKYTRQILEGMSYLHSNMIVHRDIKGA 520
Cdd:cd06625    79 IFMEYMPGGSVKDEIKAYGALTENVTRKYTRQILEGLAYLHSNMIVHRDIKGA 131

The PB1 domain is present in the two mitogen-activated protein kinase kinases MEKK2 and MEKK3 which are two members of the signaling kinase cascade involved in angiogenesis and early cardiovascular development. The PB1 domain of MEKK2 (and/or MEKK3) interacts with the PB1 domain of another member of the kinase cascade Map2k5. A canonical PB1-PB1 interaction, which involves heterodimerization of two PB1 domains, is required for the formation of macromolecular signaling complexes ensuring specificity and fidelity during cellular signaling. The interaction between two PB1 domain depends on the type of PB1. There are three types of PB1 domains: type I which contains an OPCA motif, acidic aminoacid cluster, type II which contains a basic cluster, and type I/II which contains both an OPCA motif and a basic cluster. Interactions of PB1 domains with other protein domains have been described as noncanonical PB1-interactions. The PB1 domain module is conserved in amoebas, fungi, animals, and plants. The MEKK2 and MEKK3 proteins contain a type II PB1 domain.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 2217311970  76 VRIKFEHNGERRIIAFSRPVKYEDVEHKVTTVFGQPLDLHYMNNELSILLKNQDDLDKAIDILDRSSSMKSLRILLLSQ 154
Cdd:cd06405     1 VRIKFEHNGEKRIIQFPRPVKFKDLQQKVTTAFGQPMDLHYTNNELLIPLKNQEDLDRAIELLDRSPHMKSLRILLSAP 79

Serine/threonine protein kinase [Signal transduction mechanisms];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217311970 388 NWRRGKLLGQGAFGRVYLCYDVDTGRELASKQvqFDPDSPETSKEVSALECEIQLLKNLQHERIVQYYGClrDRAEKTLT 467
Cdd:COG0515     8 RYRILRLLGRGGMGVVYLARDLRLGRPVALKV--LRPELAADPEARERFRREARALARLNHPNIVRVYDV--GEEDGRPY 83

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|.
gi 2217311970 468 IFMEYMPGGSVKDQLKAYGALTESVTRKYTRQILEGMSYLHSNMIVHRDIK 518
Cdd:COG0515    84 LVMEYVEGESLADLLRRRGPLPPAEALRILAQLAEALAAAHAAGIVHRDIK 134

PB1 domain; Phox and Bem1p domain, present in many eukaryotic cytoplasmic signalling proteins. The domain adopts a beta-grasp fold, similar to that found in ubiquitin and Ras-binding domains. A motif, variously termed OPR, PC and AID, represents the most conserved region of the majority of PB1 domains, and is necessary for PB1 domain function. This function is the formation of PB1 domain heterodimers, although not all PB1 domain pairs associate.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217311970   75 DVRIKFEHNGERRIIAFSRPVKYEDVEHKVTTVFG---QPLDLHYMNNELS-ILLKNQDDLDKAIDILDRSSSmKSLRIL 150
Cdd:smart00666   1 TVDVKLRYGGETRRLSVPRDISFEDLRSKVAKRFGldnQSFTLKYQDEDGDlVSLTSDEDLEEAIEEYDSLGS-KKLRLH 79

                   .
gi 2217311970  151 L 151
Cdd:smart00666  80 V 80

Stk1 family PASTA domain-containing Ser/Thr kinase;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 2217311970 468 IFMEYMPGGSVKDQLKAYGALTESVTRKYTRQILEGMSYLHSNMIVHRDIK 518
Cdd:NF033483   84 IVMEYVDGRTLKDYIREHGPLSPEEAVEIMIQILSALEHAHRNGIVHRDIK 134

Catalytic domain of Mitogen-Activated Protein (MAP)/Extracellular signal-Regulated Kinase (ERK) Kinase Kinase 3-like Serine/Threonine Kinases; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. This subfamily is composed of MEKK3, MEKK2, and related proteins; all contain an N-terminal PB1 domain, which mediates oligomerization, and a C-terminal catalytic domain. MEKK2 and MEKK3 are MAPK kinase kinases (MAPKKKs or MKKK) that activate MEK5 (also called MKK5), which activates ERK5. The ERK5 cascade plays roles in promoting cell proliferation, differentiation, neuronal survival, and neuroprotection. MEKK3 plays an essential role in embryonic angiogenesis and early heart development. MEKK2 and MEKK3 can also activate the MAPKs, c-Jun N-terminal kinase (JNK) and p38, through their respective MAPKKs. The MEKK3-like subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217311970 388 NWRRGKLLGQGAFGRVYLCYDVDTGRELASKQVQFDPDSPETSKEVSALECEIQLLKNLQHERIVQYYGCLRDraEKTLT 467
Cdd:cd06625     1 NWKQGKLLGQGAFGQVYLCYDADTGRELAVKQVEIDPINTEASKEVKALECEIQLLKNLQHERIVQYYGCLQD--EKSLS 78

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|...
gi 2217311970 468 IFMEYMPGGSVKDQLKAYGALTESVTRKYTRQILEGMSYLHSNMIVHRDIKGA 520
Cdd:cd06625    79 IFMEYMPGGSVKDEIKAYGALTENVTRKYTRQILEGLAYLHSNMIVHRDIKGA 131

Catalytic domain of the Serine/Threonine Kinase, Mitogen-Activated Protein (MAP)/Extracellular signal-Regulated Kinase (ERK) Kinase Kinase 2; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. MEKK2 is a MAPK kinase kinase (MAPKKK or MKKK), that phosphorylates and activates the MAPK kinase MEK5 (or MKK5), which in turn phosphorylates and activates ERK5. The ERK5 cascade plays roles in promoting cell proliferation, differentiation, neuronal survival, and neuroprotection. MEKK2 also activates ERK1/2, c-Jun N-terminal kinase (JNK) and p38 through their respective MAPKKs MEK1/2, JNK-activating kinase 2 (JNKK2), and MKK3/6. MEKK2 plays roles in T cell receptor signaling, immune synapse formation, cytokine gene expression, as well as in EGF and FGF receptor signaling. The MEKK2 subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217311970 386 PINWRRGKLLGQGAFGRVYLCYDVDTGRELASKQVQFDPDSPETSKEVSALECEIQLLKNLQHERIVQYYGCLRDRAEKT 465
Cdd:cd06652     1 PTNWRLGKLLGQGAFGRVYLCYDADTGRELAVKQVQFDPESPETSKEVNALECEIQLLKNLLHERIVQYYGCLRDPQERT 80

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 2217311970 466 LTIFMEYMPGGSVKDQLKAYGALTESVTRKYTRQILEGMSYLHSNMIVHRDIKGA 520
Cdd:cd06652    81 LSIFMEYMPGGSIKDQLKSYGALTENVTRKYTRQILEGVHYLHSNMIVHRDIKGA 135

Catalytic domain of the Serine/Threonine Kinase, Mitogen-Activated Protein Kinase Kinase Kinase; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. MAPKKKs (MKKKs or MAP3Ks) are also called MAP/ERK kinase kinases (MEKKs) in some cases. They phosphorylate and activate MAPK kinases (MAPKKs or MKKs or MAP2Ks), which in turn phosphorylate and activate MAPKs during signaling cascades that are important in mediating cellular responses to extracellular signals. This subfamily is composed of the Apoptosis Signal-regulating Kinases ASK1 (or MAPKKK5) and ASK2 (or MAPKKK6), MEKK1, MEKK2, MEKK3, MEKK4, as well as plant and fungal MAPKKKs. Also included in this subfamily are the cell division control proteins Schizosaccharomyces pombe Cdc7 and Saccharomyces cerevisiae Cdc15. The MAPKKK subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217311970 388 NWRRGKLLGQGAFGRVYLCYDVDTGRELASKQVQFDPDSPEtskEVSALECEIQLLKNLQHERIVQYYGClrDRAEKTLT 467
Cdd:cd06606     1 RWKKGELLGKGSFGSVYLALNLDTGELMAVKEVELSGDSEE---ELEALEREIRILSSLKHPNIVRYLGT--ERTENTLN 75

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|...
gi 2217311970 468 IFMEYMPGGSVKDQLKAYGALTESVTRKYTRQILEGMSYLHSNMIVHRDIKGA 520
Cdd:cd06606    76 IFLEYVPGGSLASLLKKFGKLPEPVVRKYTRQILEGLEYLHSNGIVHRDIKGA 128

Serine/Threonine protein kinases, catalytic domain; Phosphotransferases. Serine or threonine-specific kinase subfamily.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217311970  389 WRRGKLLGQGAFGRVYLCYDVDTGRELASKQVQFDpdspETSKEVSALECEIQLLKNLQHERIVQYYGCLRDraEKTLTI 468
Cdd:smart00220   1 YEILEKLGEGSFGKVYLARDKKTGKLVAIKVIKKK----KIKKDRERILREIKILKKLKHPNIVRLYDVFED--EDKLYL 74

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|
gi 2217311970  469 FMEYMPGGSVKDQLKAYGALTESVTRKYTRQILEGMSYLHSNMIVHRDIK 518
Cdd:smart00220  75 VMEYCEGGDLFDLLKKRGRLSEDEARFYLRQILSALEYLHSKGIVHRDLK 124

Catalytic domain of the Serine/Threonine Kinases, fungal Byr2-like Mitogen-Activated Protein Kinase Kinase Kinases; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. Members of this group include the MAPKKKs Schizosaccharomyces pombe Byr2, Saccharomyces cerevisiae and Cryptococcus neoformans Ste11, and related proteins. They contain an N-terminal SAM (sterile alpha-motif) domain, which mediates protein-protein interaction, and a C-terminal catalytic domain. MAPKKKs phosphorylate and activate MAPK kinases, which in turn phosphorylate and activate MAPKs during signaling cascades that are important in mediating cellular responses to extracellular signals. Fission yeast Byr2 is regulated by Ras1. It responds to pheromone signaling and controls mating through the MAPK pathway. Budding yeast Ste11 functions in MAPK cascades that regulate mating, high osmolarity glycerol, and filamentous growth responses. The Byr2 subfamily is part of a larger superfamily that includes the catalytic domains of other protein STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217311970 389 WRRGKLLGQGAFGRVYLCYDVDTGRELASKQVQFDPDSPETSKE----VSALECEIQLLKNLQHERIVQYYGCLRDraEK 464
Cdd:cd06628     2 WIKGALIGSGSFGSVYLGMNASSGELMAVKQVELPSVSAENKDRkksmLDALQREIALLRELQHENIVQYLGSSSD--AN 79

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 2217311970 465 TLTIFMEYMPGGSVKDQLKAYGALTESVTRKYTRQILEGMSYLHSNMIVHRDIKGA 520
Cdd:cd06628    80 HLNIFLEYVPGGSVATLLNNYGAFEESLVRNFVRQILKGLNYLHNRGIIHRDIKGA 135

The PB1 domain is present in the two mitogen-activated protein kinase kinases MEKK2 and MEKK3 which are two members of the signaling kinase cascade involved in angiogenesis and early cardiovascular development. The PB1 domain of MEKK2 (and/or MEKK3) interacts with the PB1 domain of another member of the kinase cascade Map2k5. A canonical PB1-PB1 interaction, which involves heterodimerization of two PB1 domains, is required for the formation of macromolecular signaling complexes ensuring specificity and fidelity during cellular signaling. The interaction between two PB1 domain depends on the type of PB1. There are three types of PB1 domains: type I which contains an OPCA motif, acidic aminoacid cluster, type II which contains a basic cluster, and type I/II which contains both an OPCA motif and a basic cluster. Interactions of PB1 domains with other protein domains have been described as noncanonical PB1-interactions. The PB1 domain module is conserved in amoebas, fungi, animals, and plants. The MEKK2 and MEKK3 proteins contain a type II PB1 domain.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 2217311970  76 VRIKFEHNGERRIIAFSRPVKYEDVEHKVTTVFGQPLDLHYMNNELSILLKNQDDLDKAIDILDRSSSMKSLRILLLSQ 154
Cdd:cd06405     1 VRIKFEHNGEKRIIQFPRPVKFKDLQQKVTTAFGQPMDLHYTNNELLIPLKNQEDLDRAIELLDRSPHMKSLRILLSAP 79

Catalytic domain of Cell division control protein 7-like Serine/Threonine Kinases; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. Members of this subfamily include Schizosaccharomyces pombe Cdc7, Saccharomyces cerevisiae Cdc15, Arabidopsis thaliana mitogen-activated protein kinase kinase kinase (MAPKKK) epsilon, and related proteins. MAPKKKs phosphorylate and activate MAPK kinases, which in turn phosphorylate and activate MAPKs during signaling cascades that are important in mediating cellular responses to extracellular signals. Fission yeast Cdc7 is essential for cell division by playing a key role in the initiation of septum formation and cytokinesis. Budding yeast Cdc15 functions to coordinate mitotic exit with cytokinesis. Arabidopsis MAPKKK epsilon is required for pollen development in the plasma membrane. The Cdc7-like subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217311970 392 GKLLGQGAFGRVYLCYDVDTGRELASKQVQFDPDSPEtskEVSALECEIQLLKNLQHERIVQYYGCLRDRAekTLTIFME 471
Cdd:cd06627     5 GDLIGRGAFGSVYKGLNLNTGEFVAIKQISLEKIPKS---DLKSVMGEIDLLKKLNHPNIVKYIGSVKTKD--SLYIILE 79

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*....
gi 2217311970 472 YMPGGSVKDQLKAYGALTESVTRKYTRQILEGMSYLHSNMIVHRDIKGA 520
Cdd:cd06627    80 YVENGSLASIIKKFGKFPESLVAVYIYQVLEGLAYLHEQGVIHRDIKGA 128

Catalytic domain of Protein Kinases; PKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine or tyrosine residues on protein substrates. PKs make up a large family of serine/threonine kinases (STKs), protein tyrosine kinases (PTKs), and dual-specificity PKs that phosphorylate both serine/threonine and tyrosine residues of target proteins. Majority of protein phosphorylation occurs on serine residues while only 1% occurs on tyrosine residues. Protein phosphorylation is a mechanism by which a wide variety of cellular proteins, such as enzymes and membrane channels, are reversibly regulated in response to certain stimuli. PKs often function as components of signal transduction pathways in which one kinase activates a second kinase, which in turn, may act on other kinases; this sequential action transmits a signal from the cell surface to target proteins, which results in cellular responses. The PK family is one of the largest known protein families with more than 100 homologous yeast enzymes and more than 500 human proteins. A fraction of PK family members are pseudokinases that lack crucial residues for catalytic activity. The mutiplicity of kinases allows for specific regulation according to substrate, tissue distribution, and cellular localization. PKs regulate many cellular processes including proliferation, division, differentiation, motility, survival, metabolism, cell-cycle progression, cytoskeletal rearrangement, immunity, and neuronal functions. Many kinases are implicated in the development of various human diseases including different types of cancer. The PK family is part of a larger superfamily that includes the catalytic domains of RIO kinases, aminoglycoside phosphotransferase, choline kinase, phosphoinositide 3-kinase (PI3K), and actin-fragmin kinase.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217311970 395 LGQGAFGRVYLCYDVDTGRELASKQVqfdpDSPETSKEVSALECEIQLLKNLQHERIVQYYGCLRDraEKTLTIFMEYMP 474
Cdd:cd00180     1 LGKGSFGKVYKARDKETGKKVAVKVI----PKEKLKKLLEELLREIEILKKLNHPNIVKLYDVFET--ENFLYLVMEYCE 74

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*
gi 2217311970 475 GGSVKDQLKAY-GALTESVTRKYTRQILEGMSYLHSNMIVHRDIK 518
Cdd:cd00180    75 GGSLKDLLKENkGPLSEEEALSILRQLLSALEYLHSNGIIHRDLK 119

The catalytic domain of CAMK family Serine/Threonine Kinases; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. CaMKs are multifunctional calcium and calmodulin (CaM) stimulated STKs involved in cell cycle regulation. There are several types of CaMKs including CaMKI, CaMKII, and CaMKIV. CaMKI proteins are monomeric and they play pivotal roles in the nervous system, including long-term potentiation, dendritic arborization, neurite outgrowth, and the formation of spines, synapses, and axons. CaMKII is a signaling molecule that translates upstream calcium and reactive oxygen species (ROS) signals into downstream responses that play important roles in synaptic function and cardiovascular physiology. CAMKIV is implicated in regulating several transcription factors like CREB, MEF2, and retinoid orphan receptors, as well as in T-cell development and signaling. The CAMK family also consists of other related kinases including the Phosphorylase kinase Gamma subunit (PhKG), the C-terminal kinase domains of Ribosomal S6 kinase (RSK) and Mitogen and stress-activated kinase (MSK), Doublecortin-like kinase (DCKL), and the MAPK-activated protein kinases MK2, MK3, and MK5, among others. The CAMK family is part of a larger superfamily that includes the catalytic domains of other protein STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217311970 392 GKLLGQGAFGRVYLCYDVDTGRELASKQVQfdpDSPETSKEVSALECEIQLLKNLQHERIVQYYGCLRDraEKTLTIFME 471
Cdd:cd05117     5 GKVLGRGSFGVVRLAVHKKTGEEYAVKIID---KKKLKSEDEEMLRREIEILKRLDHPNIVKLYEVFED--DKNLYLVME 79

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*..
gi 2217311970 472 YMPGGSVKDQLKAYGALTESVTRKYTRQILEGMSYLHSNMIVHRDIK 518
Cdd:cd05117    80 LCTGGELFDRIVKKGSFSEREAAKIMKQILSAVAYLHSQGIVHRDLK 126

Catalytic domain of STE family Protein Kinases; PKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine (ST) or tyrosine residues on protein substrates. This family is composed of STKs, and some dual-specificity PKs that phosphorylate both threonine and tyrosine residues of target proteins. Most members are kinases involved in mitogen-activated protein kinase (MAPK) signaling cascades, acting as MAPK kinases (MAPKKs), MAPKK kinases (MAPKKKs), or MAPKKK kinases (MAP4Ks). The MAPK signaling pathways are important mediators of cellular responses to extracellular signals. The pathways involve a triple kinase core cascade comprising of the MAPK, which is phosphorylated and activated by a MAPKK, which itself is phosphorylated and activated by a MAPKKK. Each MAPK cascade is activated either by a small GTP-binding protein or by an adaptor protein, which transmits the signal either directly to a MAPKKK to start the triple kinase core cascade or indirectly through a mediator kinase, a MAP4K. Other STE family members include p21-activated kinases (PAKs) and class III myosins, among others. PAKs are Rho family GTPase-regulated kinases that serve as important mediators in the function of Cdc42 (cell division cycle 42) and Rac. Class III myosins are motor proteins containing an N-terminal kinase catalytic domain and a C-terminal actin-binding domain, which can phosphorylate several cytoskeletal proteins, conventional myosin regulatory light chains, as well as autophosphorylate the C-terminal motor domain. They play an important role in maintaining the structural integrity of photoreceptor cell microvilli. The STE family is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217311970 389 WRRGKLLGQGAFGRVYLCYDVDTGRELASKQVqfDPDSPETSKEVSAlecEIQLLKNLQHERIVQYYGC-LRDRaekTLT 467
Cdd:cd05122     2 FEILEKIGKGGFGVVYKARHKKTGQIVAIKKI--NLESKEKKESILN---EIAILKKCKHPNIVKYYGSyLKKD---ELW 73

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....
gi 2217311970 468 IFMEYMPGGSVKDQLKAYGA-LTESVTRKYTRQILEGMSYLHSNMIVHRDIKGA 520
Cdd:cd05122    74 IVMEFCSGGSLKDLLKNTNKtLTEQQIAYVCKEVLKGLEYLHSHGIIHRDIKAA 127

Catalytic domain of bacterial Serine/Threonine kinases, PknB and similar proteins; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. This subfamily includes many bacterial eukaryotic-type STKs including Staphylococcus aureus PknB (also called PrkC or Stk1), Bacillus subtilis PrkC, and Mycobacterium tuberculosis Pkn proteins (PknB, PknD, PknE, PknF, PknL, and PknH), among others. S. aureus PknB is the only eukaryotic-type STK present in this species, although many microorganisms encode for several such proteins. It is important for the survival and pathogenesis of S. aureus as it is involved in the regulation of purine and pyrimidine biosynthesis, cell wall metabolism, autolysis, virulence, and antibiotic resistance. M. tuberculosis PknB is essential for growth and it acts on diverse substrates including proteins involved in peptidoglycan synthesis, cell division, transcription, stress responses, and metabolic regulation. B. subtilis PrkC is located at the inner membrane of endospores and functions to trigger spore germination. Bacterial STKs in this subfamily show varied domain architectures. The well-characterized members such as S. aureus and M. tuberculosis PknB, and B. subtilis PrkC, contain an N-terminal cytosolic kinase domain, a transmembrane (TM) segment, and mutliple C-terminal extracellular PASTA domains. The PknB subfamily is part of a larger superfamily that includes the catalytic domains of other protein STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217311970 388 NWRRGKLLGQGAFGRVYLCYDVDTGRELASKQVQFDPDSPETSKEvsALECEIQLLKNLQHERIVQYYGCLRDraEKTLT 467
Cdd:cd14014     1 RYRLVRLLGRGGMGEVYRARDTLLGRPVAIKVLRPELAEDEEFRE--RFLREARALARLSHPNIVRVYDVGED--DGRPY 76

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|.
gi 2217311970 468 IFMEYMPGGSVKDQLKAYGALTESVTRKYTRQILEGMSYLHSNMIVHRDIK 518
Cdd:cd14014    77 IVMEYVEGGSLADLLRERGPLPPREALRILAQIADALAAAHRAGIVHRDIK 127

Catalytic domain of the Serine/Threonine kinases, Liver Kinase B1, Calmodulin Dependent Protein Kinase Kinase, and similar proteins; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. Both LKB1 and CaMKKs can phosphorylate and activate AMP-activated protein kinase (AMPK). LKB1, also called STK11, serves as a master upstream kinase that activates AMPK and most AMPK-like kinases. LKB1 and AMPK are part of an energy-sensing pathway that links cell energy to metabolism and cell growth. They play critical roles in the establishment and maintenance of cell polarity, cell proliferation, cytoskeletal organization, as well as T-cell metabolism, including T-cell development, homeostasis, and effector function. CaMKKs are upstream kinases of the CaM kinase cascade that phosphorylate and activate CaMKI and CamKIV. They may also phosphorylate other substrates including PKB and AMPK. Vertebrates contain two CaMKKs, CaMKK1 (or alpha) and CaMKK2 (or beta). CaMKK1 is involved in the regulation of glucose uptake in skeletal muscles. CaMKK2 is involved in regulating energy balance, glucose metabolism, adiposity, hematopoiesis, inflammation, and cancer. The LKB1/CaMKK subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217311970 395 LGQGAFGRVYLCYDVDTGRELA---------SKQVQFDPDSPETSKEVSALECEIQLLKNLQHERIVQYYGCLRDRAEKT 465
Cdd:cd14008     1 LGRGSFGKVKLALDTETGQLYAikifnksrlRKRREGKNDRGKIKNALDDVRREIAIMKKLDHPNIVRLYEVIDDPESDK 80

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 2217311970 466 LTIFMEYMPGGSVK--DQLKAYGALTESVTRKYTRQILEGMSYLHSNMIVHRDIK 518
Cdd:cd14008    81 LYLVLEYCEGGPVMelDSGDRVPPLPEETARKYFRDLVLGLEYLHENGIVHRDIK 135

Catalytic domain of the Serine/Threonine kinase, With No Lysine (WNK) kinase; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. WNKs comprise a subfamily of STKs with an unusual placement of a catalytic lysine relative to all other protein kinases. They are critical in regulating ion balance and are thus, important components in the control of blood pressure. They are also involved in cell signaling, survival, proliferation, and organ development. WNKs are activated by hyperosmotic or low-chloride hypotonic stress and they function upstream of SPAK and OSR1 kinases, which regulate the activity of cation-chloride cotransporters through direct interaction and phosphorylation. There are four vertebrate WNKs which show varying expression patterns. WNK1 and WNK2 are widely expressed while WNK3 and WNK4 show a more restricted expression pattern. Because mutations in human WNK1 and WNK4 cause PseudoHypoAldosteronism type II (PHAII), characterized by hypertension (due to increased sodium reabsorption) and hyperkalemia (due to impaired renal potassium secretion), there are more studies conducted on these two proteins, compared to WNK2 and WNK3. The WNK subfamily is part of a larger superfamily that includes the catalytic domains of other protein STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217311970 395 LGQGAFGRVYLCYDVDTGRELASKQVQFDPDSPETSKEVSaleCEIQLLKNLQHERIVQYYGCLRDRAEKTLTIFMEYMP 474
Cdd:cd13983     9 LGRGSFKTVYRAFDTEEGIEVAWNEIKLRKLPKAERQRFK---QEIEILKSLKHPNIIKFYDSWESKSKKEVIFITELMT 85

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*.
gi 2217311970 475 GGSVKDQLKAYGALTESVTRKYTRQILEGMSYLHSNM--IVHRDIK 518
Cdd:cd13983    86 SGTLKQYLKRFKRLKLKVIKSWCRQILEGLNYLHTRDppIIHRDLK 131

Catalytic domain of the Serine/Threonine Kinases, Mammalian STe20-like protein kinase 1 and 2; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. This subfamily is composed of MST1, MST2, and related proteins including Drosophila Hippo and Dictyostelium discoideum Krs1 (kinase responsive to stress 1). MST1/2 and Hippo are involved in a conserved pathway that governs cell contact inhibition, organ size control, and tumor development. MST1 activates the mitogen-activated protein kinases (MAPKs) p38 and c-Jun N-terminal kinase (JNK) through MKK7 and MEKK1 by acting as a MAPK kinase kinase kinase. Activation of JNK by MST1 leads to caspase activation and apoptosis. MST1 has also been implicated in cell proliferation and differentiation. Krs1 may regulate cell growth arrest and apoptosis in response to cellular stress. The MST1/2 subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217311970 394 LLGQGAFGRVYLCYDVDTGRELASKQVQFDPDSPETSKEvsaleceIQLLKNLQHERIVQYYGCLRdrAEKTLTIFMEYM 473
Cdd:cd06612    10 KLGEGSYGSVYKAIHKETGQVVAIKVVPVEEDLQEIIKE-------ISILKQCDSPYIVKYYGSYF--KNTDLWIVMEYC 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*...
gi 2217311970 474 PGGSVKDQLKAYG-ALTESVTRKYTRQILEGMSYLHSNMIVHRDIKGA 520
Cdd:cd06612    81 GAGSVSDIMKITNkTLTEEEIAAILYQTLKGLEYLHSNKKIHRDIKAG 128

Catalytic domain of Plant dual-specificity Mitogen-Activated Protein Kinase Kinases and similar proteins; PKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine (ST) or tyrosine residues on protein substrates. Members of this group include MAPKKs from plants, kinetoplastids, alveolates, and mycetozoa. The MAPKK, LmxPK4, from Leishmania mexicana, is important in differentiation and virulence. Dictyostelium discoideum MEK1 is required for proper chemotaxis; MEK1 null mutants display severe defects in cell polarization and directional movement. Plants contain multiple MAPKKs like other eukaryotes. The Arabidopsis genome encodes for 10 MAPKKs while poplar and rice contain 13 MAPKKs each. The functions of these proteins have not been fully elucidated. There is evidence to suggest that MAPK cascades are involved in plant stress responses. In Arabidopsis, MKK3 plays a role in pathogen signaling; MKK2 is involved in cold and salt stress signaling; MKK4/MKK5 participates in innate immunity; and MKK7 regulates basal and systemic acquired resistance. The MAPKK subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217311970 390 RRGKLLGQGAFGRVYLCYDVDTGRELASKQVQFDpDSPETSKEVSAlecEIQLLKNLQHERIVQYYGCLRDraEKTLTIF 469
Cdd:cd06623     4 ERVKVLGQGSSGVVYKVRHKPTGKIYALKKIHVD-GDEEFRKQLLR---ELKTLRSCESPYVVKCYGAFYK--EGEISIV 77

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|
gi 2217311970 470 MEYMPGGSVKDQLKAYGALTESVTRKYTRQILEGMSYLHSNM-IVHRDIK 518
Cdd:cd06623    78 LEYMDGGSLADLLKKVGKIPEPVLAYIARQILKGLDYLHTKRhIIHRDIK 127

Catalytic domain of the Serine/Threonine Kinase, p21-activated kinase; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. PAKs are Rho family GTPase-regulated kinases that serve as important mediators in the function of Cdc42 (cell division cycle 42) and Rac. PAKs are implicated in the regulation of many cellular processes including growth factor receptor-mediated proliferation, cell polarity, cell motility, cell death and survival, and actin cytoskeleton organization. PAK deregulation is associated with tumor development. PAKs from higher eukaryotes are classified into two groups (I and II), according to their biochemical and structural features. Group I PAKs contain a PBD (p21-binding domain) overlapping with an AID (autoinhibitory domain), a C-terminal catalytic domain, SH3 binding sites and a non-classical SH3 binding site for PIX (PAK-interacting exchange factor). Group II PAKs contain a PBD and a catalytic domain, but lack other motifs found in group I PAKs. Since group II PAKs do not contain an obvious AID, they may be regulated differently from group I PAKs. Group I PAKs interact with the SH3 containing proteins Nck, Grb2 and PIX; no such binding has been demonstrated for group II PAKs. The PAK subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217311970 395 LGQGAFGRVYLCYDVDTGRELASKQVQFDPDSPETSKEvsalecEIQLLKNLQHERIVQYYGCLRDraEKTLTIFMEYMP 474
Cdd:cd06614     8 IGEGASGEVYKATDRATGKEVAIKKMRLRKQNKELIIN------EILIMKECKHPNIVDYYDSYLV--GDELWVVMEYMD 79

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*
gi 2217311970 475 GGSVKDQLKAYG-ALTESVTRKYTRQILEGMSYLHSNMIVHRDIK 518
Cdd:cd06614    80 GGSLTDIITQNPvRMNESQIAYVCREVLQGLEYLHSQNVIHRDIK 124

Catalytic domain of the Serine/Threonine kinases, Autophagy-related protein 1 and Unc-51-like kinases; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. This subfamily includes yeast ATG1 and metazoan homologs including vertebrate ULK1-3. The ATG1/ULK complex is conserved from yeast to humans and it plays a critical role in the initiation of autophagy, the intracellular system that leads to the lysosomal degradation of cellular components and their recycling into basic metabolic units. It is involved in nutrient sensing and signaling, the assembly of autophagy factors and the execution of autophagy. In metazoans, ATG1 homologs display additional functions. Unc-51 and ULKs have been implicated in neuronal and axonal development. The ATG1/ULK subfamily is part of a larger superfamily that includes the catalytic domains of other protein STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217311970 395 LGQGAFGRVYLCYDVDTGRELASKQVQFdpdSPETSKEVSALECEIQLLKNLQHERIVQYYGCLRDraEKTLTIFMEYMP 474
Cdd:cd14009     1 IGRGSFATVWKGRHKQTGEVVAIKEISR---KKLNKKLQENLESEIAILKSIKHPNIVRLYDVQKT--EDFIYLVLEYCA 75

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....
gi 2217311970 475 GGSVKDQLKAYGALTESVTRKYTRQILEGMSYLHSNMIVHRDIK 518
Cdd:cd14009    76 GGDLSQYIRKRGRLPEAVARHFMQQLASGLKFLRSKNIIHRDLK 119

Catalytic domain of the yeast Serine/Threonine Kinases, Rad53 and Cds1; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. Rad53 and Cds1 are the checkpoint kinase 2 (Chk2) homologs found in budding and fission yeast, respectively. They play a central role in the cell's response to DNA lesions to prevent genome rearrangements and maintain genome integrity. They are phosphorylated in response to DNA damage and incomplete replication, and are essential for checkpoint control. They help promote DNA repair by stalling the cell cycle prior to mitosis in the presence of DNA damage. The Rad53/Cds1 subfamily is part of a larger superfamily that includes the catalytic domains of other protein STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217311970 394 LLGQGAFGRVYLCYDVDTGRELASKQVQfDPDSPETSKEVSALECEIQLLKNLQHERIVQYYGCLRDraEKTLTIFMEYM 473
Cdd:cd14098     7 RLGSGTFAEVKKAVEVETGKMRAIKQIV-KRKVAGNDKNLQLFQREINILKSLEHPGIVRLIDWYED--DQHIYLVMEYV 83

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*
gi 2217311970 474 PGGSVKDQLKAYGALTESVTRKYTRQILEGMSYLHSNMIVHRDIK 518
Cdd:cd14098    84 EGGDLMDFIMAWGAIPEQHARELTKQILEAMAYTHSMGITHRDLK 128

Catalytic domain of Cyclin-Dependent protein Kinase-like Serine/Threonine Kinases; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. CDKs belong to a large family of STKs that are regulated by their cognate cyclins. Together, they are involved in the control of cell-cycle progression, transcription, and neuronal function. CDKs are partly regulated by their subcellular localization, which defines substrate phosphorylation and the resulting specific function. CDK1, CDK2, CDK4, and CDK6 have well-defined functions in the cell cycle, such as the regulation of the early G1 phase by CDK4 or CDK6, the G1/S phase transition by CDK2, or the entry of mitosis by CDK1. They also exhibit overlapping cyclin specificity and functions in certain conditions. Knockout mice with a single CDK deleted remain viable with specific phenotypes, showing that some CDKs can compensate for each other. For example, CDK4 can compensate for the loss of CDK6, however, double knockout mice with both CDK4 and CDK6 deleted die in utero. CDK8 and CDK9 are mainly involved in transcription while CDK5 is implicated in neuronal function. CDK7 plays essential roles in both the cell cycle as a CDK-Activating Kinase (CAK) and in transcription as a component of the general transcription factor TFIIH. The CDK-like subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217311970 395 LGQGAFGRVYLCYDVDTGRELASKQVQFDPDSPETSkeVSALEcEIQLLKNLQHERIVQyygcLRD--RAEKTLTIFMEY 472
Cdd:cd07829     7 LGEGTYGVVYKAKDKKTGEIVALKKIRLDNEEEGIP--STALR-EISLLKELKHPNIVK----LLDviHTENKLYLVFEY 79

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|.
gi 2217311970 473 MPggsvKDqLKAY-----GALTESVTRKYTRQILEGMSYLHSNMIVHRDIK 518
Cdd:cd07829    80 CD----QD-LKKYldkrpGPLPPNLIKSIMYQLLRGLAYCHSHRILHRDLK 125

Protein tyrosine and serine/threonine kinase; Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyze the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyze the reverse process. Protein kinases fall into three broad classes, characterized with respect to substrate specificity; Serine/threonine-protein kinases, tyrosine-protein kinases, and dual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins). This entry represents the catalytic domain found in a number of serine/threonine- and tyrosine-protein kinases. It does not include the catalytic domain of dual specificity kinases.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217311970 390 RRGKLLGQGAFGRVYLCY----DVDTGRELASKQVqfDPDSpeTSKEVSALECEIQLLKNLQHERIVQYYG-CLRDraeK 464
Cdd:pfam07714   2 TLGEKLGEGAFGEVYKGTlkgeGENTKIKVAVKTL--KEGA--DEEEREDFLEEASIMKKLDHPNIVKLLGvCTQG---E 74

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....
gi 2217311970 465 TLTIFMEYMPGGSVKDQLKAYG-ALTESVTRKYTRQILEGMSYLHSNMIVHRDI 517
Cdd:pfam07714  75 PLYIVTEYMPGGDLLDFLRKHKrKLTLKDLLSMALQIAKGMEYLESKNFVHRDL 128