14-3-3 domain; 14-3-3 domain is an essential part of 14-3-3 proteins, a ubiquitous class of regulatory, phosphoserine/threonine-binding proteins found in all eukaryotic cells, including yeast, protozoa and mammalian cells. 14-3-3 proteins play important roles in many biological processes that are regulated by phosphorylation, including cell cycle regulation, cell proliferation, protein trafficking, metabolic regulation and apoptosis. More than 300 binding partners of the 14-3-3 domain have been identified in all subcellular compartments and include transcription factors, signaling molecules, tumor suppressors, biosynthetic enzymes, cytoskeletal proteins and apoptosis factors. 14-3-3 binding can alter the conformation, localization, stability, phosphorylation state, activity as well as molecular interactions of a target protein. They function only as dimers, some preferring strictly homodimeric interaction, while others form heterodimers. Binding of the 14-3-3 domain to its target occurs in a phosphospecific manner where it binds to one of two consensus sequences of their target proteins; RSXpSXP (mode-1) and RXXXpSXP (mode-2). In some instances, 14-3-3 domain containing proteins are involved in regulation and signaling of a number of cellular processes in phosphorylation-independent manner. Many organisms express multiple isoforms: there are seven mammalian 14-3-3 family members (beta, gamma, eta, theta, epsilon, sigma, zeta), each encoded by a distinct gene, while plants contain up to 13 isoforms. The flexible C-terminal segment of 14-3-3 isoforms shows the highest sequence variability and may significantly contribute to individual isoform uniqueness by playing an important regulatory role by occupying the ligand binding groove and blocking the binding of inappropriate ligands in a distinct manner. Elevated amounts of 14-3-3 proteins are found in the cerebrospinal fluid of patients with Creutzfeldt-Jakob disease. In protozoa, like Plasmodium or Cryptosporidium parvum 14-3-3 proteins play an important role in key steps of parasite development.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 32693712   1 MVESMKKVAGMDVELTVEERNLLSVAYKNVIGARRASWRIISSIEQKEENKGGEDKLKMIREYRQMVETELKLICCDILD 80
Cdd:cd10020  20 MVESMKKVAGMDVELTVEERNLLSVAYKNVIGARRASWRIISSIEQKEENKGGEDKLKMIREYRQQVEKELKDICNDILD 99

                        90
                ....*....|....*.
gi 32693712  81 VLDKHLIPAANTGWQK 96
Cdd:cd10020 100 VLDKHLIPAANSGESK 115

14-3-3 epsilon, an isoform of 14-3-3 protein; 14-3-3 protein epsilon isoform (isoform (also known as tyrosine 3-monooxygenase/ tryptophan 5-monooxygenase activation protein, epsilon polypeptide) is encoded by the YWHAE gene in humans and is involved in cancer cell survival and growth. It interacts with CDC25 phosphatases, RAF1 and IRS1 proteins, suggesting its role in diverse biochemical activities related to signal transduction, such as cell division and regulation of insulin sensitivity. Overexpression of 14-3-3 epsilon in primary hepatocellular carcinoma (HCC) tissues predicts a high risk of extrahepatic metastasis and worse survival, and is a potential therapeutic target. It has also been implicated in the pathogenesis of small cell lung cancer. 14-3-3 epsilon overexpression protects colorectal cancer and endothelial cells from oxidative stress-induced apoptosis, while its suppression by non-steroidal anti-inflammatory drugs induces cancer and endothelial cell death. Cellular levels of 14-3-3 epsilon could possibly serve as an important regulator of cell survival in response to oxidative stress and other death signals. 14-3-3 domains are an essential part of 14-3-3 proteins, a ubiquitous class of regulatory, phosphoserine/threonine-binding proteins found in all eukaryotic cells, including yeast, protozoa and mammalian cells.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 32693712   1 MVESMKKVAGMDVELTVEERNLLSVAYKNVIGARRASWRIISSIEQKEENKGGEDKLKMIREYRQMVETELKLICCDILD 80
Cdd:cd10020  20 MVESMKKVAGMDVELTVEERNLLSVAYKNVIGARRASWRIISSIEQKEENKGGEDKLKMIREYRQQVEKELKDICNDILD 99

                        90
                ....*....|....*.
gi 32693712  81 VLDKHLIPAANTGWQK 96
Cdd:cd10020 100 VLDKHLIPAANSGESK 115

14-3-3 family protein [Signal transduction mechanisms];

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 32693712   1 MVESMKKVAGMDVELTVEERNLLSVAYKNVIGARRASWRIISSIEQKEENKGGEDKLKMIREYRQMVETELKLICCDILD 80
Cdd:COG5040  24 MVENMKLVASSGQELSVEERNLLSVAYKNVIGARRASWRIVSSIEQKEESKGNTHQVELIKEYRKKIETELTKICDDILS 103

                        90
                ....*....|....*.
gi 32693712  81 VLDKHLIPAANTGWQK 96
Cdd:COG5040 104 VLEKHLIPAATTGESK 119

14-3-3 epsilon, an isoform of 14-3-3 protein; 14-3-3 protein epsilon isoform (isoform (also known as tyrosine 3-monooxygenase/ tryptophan 5-monooxygenase activation protein, epsilon polypeptide) is encoded by the YWHAE gene in humans and is involved in cancer cell survival and growth. It interacts with CDC25 phosphatases, RAF1 and IRS1 proteins, suggesting its role in diverse biochemical activities related to signal transduction, such as cell division and regulation of insulin sensitivity. Overexpression of 14-3-3 epsilon in primary hepatocellular carcinoma (HCC) tissues predicts a high risk of extrahepatic metastasis and worse survival, and is a potential therapeutic target. It has also been implicated in the pathogenesis of small cell lung cancer. 14-3-3 epsilon overexpression protects colorectal cancer and endothelial cells from oxidative stress-induced apoptosis, while its suppression by non-steroidal anti-inflammatory drugs induces cancer and endothelial cell death. Cellular levels of 14-3-3 epsilon could possibly serve as an important regulator of cell survival in response to oxidative stress and other death signals. 14-3-3 domains are an essential part of 14-3-3 proteins, a ubiquitous class of regulatory, phosphoserine/threonine-binding proteins found in all eukaryotic cells, including yeast, protozoa and mammalian cells.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 32693712   1 MVESMKKVAGMDVELTVEERNLLSVAYKNVIGARRASWRIISSIEQKEENKGGEDKLKMIREYRQMVETELKLICCDILD 80
Cdd:cd10020  20 MVESMKKVAGMDVELTVEERNLLSVAYKNVIGARRASWRIISSIEQKEENKGGEDKLKMIREYRQQVEKELKDICNDILD 99

                        90
                ....*....|....*.
gi 32693712  81 VLDKHLIPAANTGWQK 96
Cdd:cd10020 100 VLDKHLIPAANSGESK 115

14-3-3 protein;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 32693712     1 MVESMKKVAGMDVELTVEERNLLSVAYKNVIGARRASWRIISSIEQKEENkGGEDKLKMIREYRQMVETELKLICCDILD 80
Cdd:pfam00244  14 MVEYMKKVVELGPELTVEERNLLSVAYKNVVGARRASWRVLSSIEQKEES-GNEKKVALIKEYREKIEKELKDICNDVLD 92

                          90
                  ....*....|...
gi 32693712    81 VLDKHLIPAANTG 93
Cdd:pfam00244  93 LIDKYLIPNATDG 105

14-3-3 domain; 14-3-3 domain is an essential part of 14-3-3 proteins, a ubiquitous class of regulatory, phosphoserine/threonine-binding proteins found in all eukaryotic cells, including yeast, protozoa and mammalian cells. 14-3-3 proteins play important roles in many biological processes that are regulated by phosphorylation, including cell cycle regulation, cell proliferation, protein trafficking, metabolic regulation and apoptosis. More than 300 binding partners of the 14-3-3 domain have been identified in all subcellular compartments and include transcription factors, signaling molecules, tumor suppressors, biosynthetic enzymes, cytoskeletal proteins and apoptosis factors. 14-3-3 binding can alter the conformation, localization, stability, phosphorylation state, activity as well as molecular interactions of a target protein. They function only as dimers, some preferring strictly homodimeric interaction, while others form heterodimers. Binding of the 14-3-3 domain to its target occurs in a phosphospecific manner where it binds to one of two consensus sequences of their target proteins; RSXpSXP (mode-1) and RXXXpSXP (mode-2). In some instances, 14-3-3 domain containing proteins are involved in regulation and signaling of a number of cellular processes in phosphorylation-independent manner. Many organisms express multiple isoforms: there are seven mammalian 14-3-3 family members (beta, gamma, eta, theta, epsilon, sigma, zeta), each encoded by a distinct gene, while plants contain up to 13 isoforms. The flexible C-terminal segment of 14-3-3 isoforms shows the highest sequence variability and may significantly contribute to individual isoform uniqueness by playing an important regulatory role by occupying the ligand binding groove and blocking the binding of inappropriate ligands in a distinct manner. Elevated amounts of 14-3-3 proteins are found in the cerebrospinal fluid of patients with Creutzfeldt-Jakob disease. In protozoa, like Plasmodium or Cryptosporidium parvum 14-3-3 proteins play an important role in key steps of parasite development.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 32693712   1 MVESMKKVAGMDVELTVEERNLLSVAYKNVIGARRASWRIISSIEQKEENKGGEDKLKMIREYRQMVETELKLICCDILD 80
Cdd:cd08774  19 MVKYMKQVAELNGELTKEERNLLSVAYKNVVGSRRASWRILSSIEQKESSKGNEEKLKLIKEYKEKIEKELKDICNDILD 98

                        90
                ....*....|...
gi 32693712  81 VLDKHLIPAANTG 93
Cdd:cd08774  99 LIDKHLIPSATDP 111

14-3-3 homologues; 14-3-3 homologues mediates signal transduction by binding to phosphoserine-containing proteins. They are involved in growth factor signalling and also interact with MEK kinases.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 32693712      1 MVESMKKVA-GMDV-ELTVEERNLLSVAYKNVIGARRASWRIISSIEQKEENKGGEDKLKMIREYRQMVETELKLICCDI 78
Cdd:smart00101  20 MVEFMEKVAkTVDSeELTVEERNLLSVAYKNVIGARRASWRIISSIEQKEESRGNEDHVASIKEYRGKIETELSKICDGI 99

                           90
                   ....*....|....*...
gi 32693712     79 LDVLDKHLIPAANTGWQK 96
Cdd:smart00101 100 LKLLESHLIPSASAAESK 117

14-3-3 beta and zeta isoforms of 14-3-3 protein; 14-3-3 protein beta and zeta isoform (also known as tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, beta and zeta polypeptide) are encoded by the YWHAB gene and YWHAZ gene in humans. They have been linked to mitogenic signaling and the cell cycle machinery, and to cancer initiation and progression, respectively. The beta isoform has been shown to interact with RAF1 and CDC25 phosphatases and its overexpression is associated with invasion, migration, metastasis and proliferation of tumor cells and its elevated levels are correlated with tumor size, the number of lymph node metastases and a reduced survival rate. It is significantly overexpressed in lung cancer tissues, mutated chronic lymphocytic leukemia (M-CLL), gastric cancer tissues, aflatoxin B1-induced rat hepatocellular carcinoma K1 and K2 cells, as well as renal cell carcinoma cysts, and can potentially be used as a diagnostic and prognostic biomarker in the cancer. Numerous proteins involved in anti-apoptosis and tumor progression were also found to be differentially expressed in gastric cancer cells where 14-3-3 beta is overexpressed. 14-3-3 beta also interacts with human Dapper1 (hDpr1), a key negative regulator of Wnt signaling, via hDpr1 phosphorylation by protein kinase A, thus attenuating the ability of hDpr1 to promote Dishevelled (Dvl) degradation, and subsequently enhancing Wnt signaling. The zeta isoform is ubiquitously expressed and localized to most subcellular regions, including the cytoplasm, plasma membrane, mitochondria, and nucleus. Its overexpression and gene amplification in multiple cancers are correlated with poor prognosis and chemoresistance in cancer patients. 14-3-3 zeta has been identified as a biomarker with high sensitivity and specificity for diagnosis and prognosis in multiple tumor types, including hepatocellular carcinoma, head and neck cancer, indicating a potential clinical application for using 14-3-3 zeta in selecting treatment options and predicting cancer outcome. It also interacts with IRS1 protein, suggesting a role in regulating insulin sensitivity. 14-3-3 domains are an essential part of 14-3-3 proteins, a ubiquitous class of regulatory, phosphoserine/threonine-binding proteins found in all eukaryotic cells, including yeast, protozoa and mammalian cells.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 32693712   1 MVESMKKVAGMDVELTVEERNLLSVAYKNVIGARRASWRIISSIEQKEEnkGGEDKLKMIREYRQMVETELKLICCDILD 80
Cdd:cd10022  21 MAACMKAVTEQGAELSNEERNLLSVAYKNVVGARRSSWRVVSSIEQKTE--GAEKKQQMAREYREKIETELRDICNDVLS 98

                        90
                ....*....|.
gi 32693712  81 VLDKHLIPAAN 91
Cdd:cd10022  99 LLEKFLIPNAS 109

14-3-3 sigma, an isoform of 14-3-3 protein; 14-3-3 protein sigma isoform, also known as stratifin or human mammary epithelial marker (HME) 1, has been most directly linked to tumor development. In humans, it is expressed by the SFN gene, strictly in stratified squamous epithelial cells in response to DNA damage where it is transcriptionally induced in a p53-dependent manner, subsequently causing cell-cycle arrest at the G2/M checkpoint. Up-regulation and down-regulation of 14-3-3 sigma expression have both been described in tumors. For example, in human breast cancer, 14-3-3 sigma is predominantly down-regulated by CpG methylation, acting as both a tumor suppressor and a prognostic indicator, while in human scirrhous-type gastric carcinoma (SGC), it is up-regulated and may play an important role in SGC carcinogenesis and progression. Loss of 14-3-3 sigma expression sensitizes tumor cells to treatment with conventional cytostatic drugs, making this protein an attractive therapeutic target. 14-3-3 domains are an essential part of 14-3-3 proteins, a ubiquitous class of regulatory, phosphoserine/threonine-binding proteins found in all eukaryotic cells, including yeast, protozoa and mammalian cells.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 32693712   1 MVESMKKVAGMDVELTVEERNLLSVAYKNVIGARRASWRIISSIEQKEENKGGEDKLKMIREYRQMVETELKLICCDILD 80
Cdd:cd10019  22 MAAFMKGAVEKGEELSNEERNLLSVAYKNVVGGQRAAWRVLSSIEQKSNEEGSEEKGPEVREYREKVETELQGVCDTVLG 101

                        90
                ....*....|
gi 32693712  81 VLDKHLIPAA 90
Cdd:cd10019 102 LLDSHLIKEA 111

14-3-3 eta, an isoform of 14-3-3 protein; 14-3-3 eta isoform (also known as tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, eta polypeptide) is expressed mainly in brain, and is involved in hypothalamic-pituitary-adrenocortical (HPA) axis regulation. In humans, it is encoded by the YWHAH gene, and is a positional and functional candidate for schizophrenia as well as bipolar disorder (BP). This gene contains a 7 bp repeat sequence in its 5' Untranslated Region (UTR), and early-onset schizophrenia has been associated with changes in the number of this repeat. 14-3-3 eta and gamma are found in the serum and synovial fluid of patients with joint inflammation. Specifically, 14-3-3 eta, which plays a regulatory role in chondrogenic differentiation, is significantly overexpressed in juvenile rheumatoid arthritis (JRA), a chronic inflammatory disease often associated with growth impairment. Overexpression of Gremlin 1, the bone morphogenetic protein antagonist, may play an oncogenic role in carcinomas of the uterine cervix, lung, ovary, kidney, breast, colon, pancreas, and sarcoma, since it functions by interaction with the 14-3-3 eta domain. Therefore, Gremlin 1 and its binding protein 14-3-3 eta could be appropriate targets for developing diagnostic and therapeutic strategies against human cancers. 14-3-3 domain is an essential part of 14-3-3 proteins, a ubiquitous class of regulatory, phosphoserine/threonine-binding proteins found in all eukaryotic cells, including yeast, protozoa and mammalian cells.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 32693712   1 MVESMKKVAGMDVELTVEERNLLSVAYKNVIGARRASWRIISSIEQKEENKGGEDKLKMIREYRQMVETELKLICCDILD 80
Cdd:cd10025  21 MASAMKSVTELNEPLSNEDRNLLSVAYKNVVGARRSSWRVISSIEQKTMADGNEKKLEKVKAYREKIEKELETVCNDVLA 100

                        90
                ....*....|.
gi 32693712  81 VLDKHLIPAAN 91
Cdd:cd10025 101 LLDKFLIKNCN 111