FERM domain C-lobe of Janus kinase (JAK) 2; JAK2 has been implicated in signaling by members of the type II cytokine receptor family, the GM-CSF receptor family, the gp130 receptor family, and the single chain receptors. JAK2 orthologs have been identified in all mammals. Mutations in JAK2 have been implicated in polycythemia vera, essential thrombocythemia, myelofibrosis as well as other myeloproliferative disorders. JAK2 gene fusions with the PCM1 and TEL(ETV6) (TEL-JAK2) genes have been found in leukemia patients. Researcher are targetting JAK2 inhibitors in the treatment of patients with prostate cancer. JAK2 has been shown to interact with a variety of proteins including growth hormone receptor, STAT5A, STAT5B, interleukin 5 receptor alpha subunit, interleukin 12 receptor, SOCS3, PTPN6,PTPN11, Grb2, VAV1, and YES1. JAK (also called Just Another Kinase) is a family of intracellular, non-receptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway. The JAK family in mammals consists of 4 members: JAK1, JAK2, JAK3 and TYK2. JAKs are composed of seven JAK homology (JH) domains (JH1-JH7) . The C-terminal JH1 domain is the main catalytic domain, followed by JH2, which is often referred to as a pseudokinase domain, followed by JH3-JH4 which is homologous to the SH2 domain, and lastly JH5-JH7 which is a FERM domain. Named after Janus, the two-faced Roman god of doorways, JAKs possess two near-identical phosphate-transferring domains; one which displays the kinase activity (JH1), while the other negatively regulates the kinase activity of the first (JH2). The FERM domain has a cloverleaf tripart structure composed of: (1) FERM_N (A-lobe or F1); (2) FERM_M (B-lobe, or F2); and (3) FERM_C (C-lobe or F3). The C-lobe/F3 within the FERM domain is part of the PH domain family. The FERM domain is found in the cytoskeletal-associated proteins such as ezrin, moesin, radixin, 4.1R, and merlin. These proteins provide a link between the membrane and cytoskeleton and are involved in signal transduction pathways. The FERM domain is also found in protein tyrosine phosphatases (PTPs), the tyrosine kinases FAK and JAK, in addition to other proteins involved in signaling. This domain is structurally similar to the PH and PTB domains and consequently is capable of binding to both peptides and phospholipids at different sites.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907131829 266 YTEQFEVKESargpsgEEIFATIIITGNGGIQWSRGKHKESETltEQDVQLYCDFPDIIDVSIKQANQECSNESRIVTVH 345
Cdd:cd13333     1 YSERFEVKEP------SEGQVTIVVTGNGGIQWSRGKHKETEA--EQDLQTYCDFPEVIDISIKQANKEGSSESRVVTIN 72

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|.
gi 1907131829 346 KQDGKVLEIELSSLKEALSFVSLIDGYYRLTADAHHYLCKE 386
Cdd:cd13333    73 KQDGKNLELEFSSLSEALSFVSLIDGYYRLTTDAHHYLCKE 113

FERM F1 ubiquitin-like domain; This is an F1 lobe domain consisting of a ubiquitin like fold found in FERM region of Jak-family tyrosine kinases. Multidomain JAK molecules interact with receptors through their FERM and SH2-like domains, triggering a series of phosphorylation events, resulting in the activation of their kinase domains. Overall, the FERM region maintains the typical three-lobed architecture, with an F1 lobe consisting of a ubiquitin-like fold, an F2 lobe consisting of an acyl-CoA binding protein fold, and an F3 lobe consisting of a pleckstrin-homology (PH) fold.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907131829  39 LQVYLYHSLGQAEGEYLKFPSGEYVAEEICVAASKACGITPVYHNMFALMSETERIWYPPNHVFHIDESTRHDILYRIRF 118
Cdd:pfam18379   1 LQVHLYWSGPGDGETYLSYPPGEYTAEELCIDAAKACGITPVYHNLFALYDEDDRVWYPPNHVFHIDESTSLTLHFRIRF 80

                          90
                  ....*....|....*.
gi 1907131829 119 YFPHWYCSGSSRTYRY 134
Cdd:pfam18379  81 YFPNWHGLGESEPYRY 96

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
                  ....*....|....*....|....*....|....*....|....*...
gi 1907131829 545 LIFNESLGQGTFTKIFKGVRREVGDYGQLHKTEVLLKVLDKAHRNYSE 592
Cdd:cd05078     1 LIFNESLGQGTFTKIFKGIRREVGDYGQLHETEVLLKVLDKAHRNYSE 48

FERM domain C-lobe of Janus kinase (JAK) 2; JAK2 has been implicated in signaling by members of the type II cytokine receptor family, the GM-CSF receptor family, the gp130 receptor family, and the single chain receptors. JAK2 orthologs have been identified in all mammals. Mutations in JAK2 have been implicated in polycythemia vera, essential thrombocythemia, myelofibrosis as well as other myeloproliferative disorders. JAK2 gene fusions with the PCM1 and TEL(ETV6) (TEL-JAK2) genes have been found in leukemia patients. Researcher are targetting JAK2 inhibitors in the treatment of patients with prostate cancer. JAK2 has been shown to interact with a variety of proteins including growth hormone receptor, STAT5A, STAT5B, interleukin 5 receptor alpha subunit, interleukin 12 receptor, SOCS3, PTPN6,PTPN11, Grb2, VAV1, and YES1. JAK (also called Just Another Kinase) is a family of intracellular, non-receptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway. The JAK family in mammals consists of 4 members: JAK1, JAK2, JAK3 and TYK2. JAKs are composed of seven JAK homology (JH) domains (JH1-JH7) . The C-terminal JH1 domain is the main catalytic domain, followed by JH2, which is often referred to as a pseudokinase domain, followed by JH3-JH4 which is homologous to the SH2 domain, and lastly JH5-JH7 which is a FERM domain. Named after Janus, the two-faced Roman god of doorways, JAKs possess two near-identical phosphate-transferring domains; one which displays the kinase activity (JH1), while the other negatively regulates the kinase activity of the first (JH2). The FERM domain has a cloverleaf tripart structure composed of: (1) FERM_N (A-lobe or F1); (2) FERM_M (B-lobe, or F2); and (3) FERM_C (C-lobe or F3). The C-lobe/F3 within the FERM domain is part of the PH domain family. The FERM domain is found in the cytoskeletal-associated proteins such as ezrin, moesin, radixin, 4.1R, and merlin. These proteins provide a link between the membrane and cytoskeleton and are involved in signal transduction pathways. The FERM domain is also found in protein tyrosine phosphatases (PTPs), the tyrosine kinases FAK and JAK, in addition to other proteins involved in signaling. This domain is structurally similar to the PH and PTB domains and consequently is capable of binding to both peptides and phospholipids at different sites.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907131829 266 YTEQFEVKESargpsgEEIFATIIITGNGGIQWSRGKHKESETltEQDVQLYCDFPDIIDVSIKQANQECSNESRIVTVH 345
Cdd:cd13333     1 YSERFEVKEP------SEGQVTIVVTGNGGIQWSRGKHKETEA--EQDLQTYCDFPEVIDISIKQANKEGSSESRVVTIN 72

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|.
gi 1907131829 346 KQDGKVLEIELSSLKEALSFVSLIDGYYRLTADAHHYLCKE 386
Cdd:cd13333    73 KQDGKNLELEFSSLSEALSFVSLIDGYYRLTTDAHHYLCKE 113

FERM F1 ubiquitin-like domain; This is an F1 lobe domain consisting of a ubiquitin like fold found in FERM region of Jak-family tyrosine kinases. Multidomain JAK molecules interact with receptors through their FERM and SH2-like domains, triggering a series of phosphorylation events, resulting in the activation of their kinase domains. Overall, the FERM region maintains the typical three-lobed architecture, with an F1 lobe consisting of a ubiquitin-like fold, an F2 lobe consisting of an acyl-CoA binding protein fold, and an F3 lobe consisting of a pleckstrin-homology (PH) fold.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907131829  39 LQVYLYHSLGQAEGEYLKFPSGEYVAEEICVAASKACGITPVYHNMFALMSETERIWYPPNHVFHIDESTRHDILYRIRF 118
Cdd:pfam18379   1 LQVHLYWSGPGDGETYLSYPPGEYTAEELCIDAAKACGITPVYHNLFALYDEDDRVWYPPNHVFHIDESTSLTLHFRIRF 80

                          90
                  ....*....|....*.
gi 1907131829 119 YFPHWYCSGSSRTYRY 134
Cdd:pfam18379  81 YFPNWHGLGESEPYRY 96

Band 4.1 homologues; Also known as ezrin/radixin/moesin (ERM) protein domains. Present in myosins, ezrin, radixin, moesin, protein tyrosine phosphatases. Plasma membrane-binding domain. These proteins play structural and regulatory roles in the assembly and stabilization of specialized plasmamembrane domains. Some PDZ domain containing proteins bind one or more of this family. Now includes JAKs.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907131829   38 VLQVYLYHslgqaeGEYLKFPSG-EYVAEEICVAASKACGItpVYHNMFALM----SETERIWY-PPNHVFHIDESTRHD 111
Cdd:smart00295   1 VLKVYLLD------GTTLEFEVDsSTTAEELLETVCRKLGI--RESEYFGLQfedpDEDLRHWLdPAKTLLDQDVKSEPL 72

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907131829  112 IL-YRIRFYFPHwycsgssrtyrygvsrgAEAPLLDDFVMSYLFAQWRHDFVHGWIKVPvthetQEECLGMAVLDMMRIA 190
Cdd:smart00295  73 TLyFRVKFYPPD-----------------PNQLKEDPTRLNLLYLQVRNDILEGRLPCP-----EEEALLLAALALQAEF 130

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907131829  191 KEKDQTPLAVYNSVSYKTFLPKCV---------RAKIQDYHiltrkriryrfrrfiQQFsqCKATARNLKLKYLINLETL 261
Cdd:smart00295 131 GDYDEELHDLRGELSLKRFLPKQLldsrklkewRERIVELH---------------KEL--IGLSPEEAKLKYLELARKL 193

                   ....*....
gi 1907131829  262 qSAFYTEQF 270
Cdd:smart00295 194 -PTYGVELF 201

Pseudokinase (repeat 1) domain of the Protein Tyrosine Kinase, Janus kinase 2; Jak2 is widely expressed in many tissues. It is essential for the signaling of hormone-like cytokines such as growth hormone, erythropoietin, thrombopoietin, and prolactin, as well as some IFNs and cytokines that signal through the IL-3 and gp130 receptors. Disruption of Jak2 in mice results in an embryonic lethal phenotype with multiple defects including erythropoietic and cardiac abnormalities. It is the only Jak gene that results in a lethal phenotype when disrupted in mice. A mutation in the pseudokinase domain of Jak2, V617F, is present in many myeloproliferative diseases, including almost all patients with polycythemia vera, and 50% of patients with essential thrombocytosis and myelofibrosis. Jak2 is a cytoplasmic (or nonreceptor) PTK containing an N-terminal FERM domain, followed by a Src homology 2 (SH2) domain, a pseudokinase domain, and a C-terminal tyr kinase domain. The pseudokinase domain shows similarity to tyr kinases but lacks crucial residues for catalytic activity and ATP binding. Despite this, the presumed pseudokinase (repeat 1) domain of Jak2 exhibits dual-specificity kinase activity, phosphorylating two negative regulatory sites in Jak2: Ser523 and Tyr570. Inactivation of the repeat 1 domain increased Jak2 basal activity, suggesting that it modulates the kinase activity of the C-terminal catalytic (repeat 2) domain. The Jak2 subfamily is part of a larger superfamily that includes the catalytic domains of other kinases such as serine/threonine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*...
gi 1907131829 545 LIFNESLGQGTFTKIFKGVRREVGDYGQLHKTEVLLKVLDKAHRNYSE 592
Cdd:cd05078     1 LIFNESLGQGTFTKIFKGIRREVGDYGQLHETEVLLKVLDKAHRNYSE 48

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
                  ....*....|....*....|....*....|....*....|....
gi 1907131829 545 LIFNESLGQGTFTKIFKGVRRevgDYGQLHKTEVLLKVLDKAHR 588
Cdd:pfam07714   1 LTLGEKLGEGAFGEVYKGTLK---GEGENTKIKVAVKTLKEGAD 41

FERM domain C-lobe of Janus kinase (JAK) 2; JAK2 has been implicated in signaling by members of the type II cytokine receptor family, the GM-CSF receptor family, the gp130 receptor family, and the single chain receptors. JAK2 orthologs have been identified in all mammals. Mutations in JAK2 have been implicated in polycythemia vera, essential thrombocythemia, myelofibrosis as well as other myeloproliferative disorders. JAK2 gene fusions with the PCM1 and TEL(ETV6) (TEL-JAK2) genes have been found in leukemia patients. Researcher are targetting JAK2 inhibitors in the treatment of patients with prostate cancer. JAK2 has been shown to interact with a variety of proteins including growth hormone receptor, STAT5A, STAT5B, interleukin 5 receptor alpha subunit, interleukin 12 receptor, SOCS3, PTPN6,PTPN11, Grb2, VAV1, and YES1. JAK (also called Just Another Kinase) is a family of intracellular, non-receptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway. The JAK family in mammals consists of 4 members: JAK1, JAK2, JAK3 and TYK2. JAKs are composed of seven JAK homology (JH) domains (JH1-JH7) . The C-terminal JH1 domain is the main catalytic domain, followed by JH2, which is often referred to as a pseudokinase domain, followed by JH3-JH4 which is homologous to the SH2 domain, and lastly JH5-JH7 which is a FERM domain. Named after Janus, the two-faced Roman god of doorways, JAKs possess two near-identical phosphate-transferring domains; one which displays the kinase activity (JH1), while the other negatively regulates the kinase activity of the first (JH2). The FERM domain has a cloverleaf tripart structure composed of: (1) FERM_N (A-lobe or F1); (2) FERM_M (B-lobe, or F2); and (3) FERM_C (C-lobe or F3). The C-lobe/F3 within the FERM domain is part of the PH domain family. The FERM domain is found in the cytoskeletal-associated proteins such as ezrin, moesin, radixin, 4.1R, and merlin. These proteins provide a link between the membrane and cytoskeleton and are involved in signal transduction pathways. The FERM domain is also found in protein tyrosine phosphatases (PTPs), the tyrosine kinases FAK and JAK, in addition to other proteins involved in signaling. This domain is structurally similar to the PH and PTB domains and consequently is capable of binding to both peptides and phospholipids at different sites.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907131829 266 YTEQFEVKESargpsgEEIFATIIITGNGGIQWSRGKHKESETltEQDVQLYCDFPDIIDVSIKQANQECSNESRIVTVH 345
Cdd:cd13333     1 YSERFEVKEP------SEGQVTIVVTGNGGIQWSRGKHKETEA--EQDLQTYCDFPEVIDISIKQANKEGSSESRVVTIN 72

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|.
gi 1907131829 346 KQDGKVLEIELSSLKEALSFVSLIDGYYRLTADAHHYLCKE 386
Cdd:cd13333    73 KQDGKNLELEFSSLSEALSFVSLIDGYYRLTTDAHHYLCKE 113

FERM F1 ubiquitin-like domain; This is an F1 lobe domain consisting of a ubiquitin like fold found in FERM region of Jak-family tyrosine kinases. Multidomain JAK molecules interact with receptors through their FERM and SH2-like domains, triggering a series of phosphorylation events, resulting in the activation of their kinase domains. Overall, the FERM region maintains the typical three-lobed architecture, with an F1 lobe consisting of a ubiquitin-like fold, an F2 lobe consisting of an acyl-CoA binding protein fold, and an F3 lobe consisting of a pleckstrin-homology (PH) fold.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907131829  39 LQVYLYHSLGQAEGEYLKFPSGEYVAEEICVAASKACGITPVYHNMFALMSETERIWYPPNHVFHIDESTRHDILYRIRF 118
Cdd:pfam18379   1 LQVHLYWSGPGDGETYLSYPPGEYTAEELCIDAAKACGITPVYHNLFALYDEDDRVWYPPNHVFHIDESTSLTLHFRIRF 80

                          90
                  ....*....|....*.
gi 1907131829 119 YFPHWYCSGSSRTYRY 134
Cdd:pfam18379  81 YFPNWHGLGESEPYRY 96

FERM domain C-lobe of Janus kinase (JAK); JAK (also called Just Another Kinase) is a family of intracellular, non-receptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway. The JAK family in mammals consists of 4 members: JAK1, JAK2, JAK3 and TYK2. JAKs are composed of seven JAK homology (JH) domains (JH1-JH7) . The C-terminal JH1 domain is the main catalytic domain, followed by JH2, which is often referred to as a pseudokinase domain, followed by JH3-JH4 which is homologous to the SH2 domain, and lastly JH5-JH7 which is a FERM domain. Named after Janus, the two-faced Roman god of doorways, JAKs possess two near-identical phosphate-transferring domains; one which displays the kinase activity (JH1), while the other negatively regulates the kinase activity of the first (JH2). The FERM domain has a cloverleaf tripart structure composed of: (1) FERM_N (A-lobe or F1); (2) FERM_M (B-lobe, or F2); and (3) FERM_C (C-lobe or F3). The C-lobe/F3 within the FERM domain is part of the PH domain family. The FERM domain is found in the cytoskeletal-associated proteins such as ezrin, moesin, radixin, 4.1R, and merlin. These proteins provide a link between the membrane and cytoskeleton and are involved in signal transduction pathways. The FERM domain is also found in protein tyrosine phosphatases (PTPs), the tyrosine kinases FAK and JAK, in addition to other proteins involved in signaling. This domain is structurally similar to the PH and PTB domains and consequently is capable of binding to both peptides and phospholipids at different sites.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907131829 266 YTEQFEVKESARG-PSGEEIFATIIITGNGGIQWSRGKHKESetlteqDVQLYCDFPDIIDVSIKQanqecsnESRIVTV 344
Cdd:cd13196     1 LSEKYKATMLEGGsKEASEIPVEVLVSGDEGIKWLRTPNTES------DWQTLCDIPELCHISIKQ-------ESGTVEI 67

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|..
gi 1907131829 345 HKQDGKVLEIELSSLKEALSFVSLIDGYYRLTADAHHYLCKE 386
Cdd:cd13196    68 SRKDGKPLELEFSSHAEALSFVSLVDGYYRLTCDWTHYLCKD 109

Src homology 2 (SH2) domain in the Janus kinase (Jak) family; The Janus kinases (Jak) are a family of 4 non-receptor tyrosine kinases (Jak1, Jak2, Jak3, Tyk2) which respond to cytokine or growth factor receptor activation. To transduce cytokine signaling, a series of conformational changes occur in the receptor-Jak complex upon extracellular ligand binding. This results in trans-activation of the receptor-associated Jaks followed by phosphorylation of receptor tail tyrosine sites. The Signal Transducers and Activators of Transcription (STAT) are then recruited to the receptor tail, become phosphorylated and translocate to the nucleus to regulate transcription. Jaks have four domains: the pseudokinase domain, the catalytic tyrosine kinase domain, the FERM (band four-point-one, ezrin, radixin, and moesin) domain, and the SH2 (Src Homology-2) domain. The Jak kinases are regulated by several enzymatic and non-enzymatic mechanisms. First, the Jak kinase domain is regulated by phosphorylation of the activation loop which is associated with the catalytically competent kinase conformation and is distinct from the inactive kinase conformation. Second, the pseudokinase domain directly modulates Jak catalytic activity with the FERM domain maintaining an active state. Third, the suppressor of cytokine signaling (SOCS) family and tyrosine phosphatases directly regulate Jak activity. Dysregulation of Jak activity can manifest as either a reduction or an increase in kinase activity resulting in immunodeficiency, inflammatory diseases, hematological defects, autoimmune and myeloproliferative disorders, and susceptibility to infection. Altered Jak regulation occurs by many mechanisms, including: gene translocations, somatic or inherited point mutations, receptor mutations, and alterations in the activity of Jak regulators such as SOCS or phosphatases. 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 1907131829 386 EVAPPAVLENIHSNCHGPISMDFAISKLKKAGNQTGLYVLRCSPKDFNKYFLTFAVERENVIEYKHCLITKNENGEYNLS 465
Cdd:cd09921     1 DVATPSLVELIELRCHGPIGGEFSYRKLKERGNKPGSYILRESETEYDTYYIDVCVKDGSRFQTKTFKIEKKEGGVFFLD 80

                          90
                  ....*....|....*..
gi 1907131829 466 GTKRNFSNLKDLLNCYQ 482
Cdd:cd09921    81 GDSREYPSLRDLLNSLQ 97

Band 4.1 homologues; Also known as ezrin/radixin/moesin (ERM) protein domains. Present in myosins, ezrin, radixin, moesin, protein tyrosine phosphatases. Plasma membrane-binding domain. These proteins play structural and regulatory roles in the assembly and stabilization of specialized plasmamembrane domains. Some PDZ domain containing proteins bind one or more of this family. Now includes JAKs.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907131829   38 VLQVYLYHslgqaeGEYLKFPSG-EYVAEEICVAASKACGItpVYHNMFALM----SETERIWY-PPNHVFHIDESTRHD 111
Cdd:smart00295   1 VLKVYLLD------GTTLEFEVDsSTTAEELLETVCRKLGI--RESEYFGLQfedpDEDLRHWLdPAKTLLDQDVKSEPL 72

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907131829  112 IL-YRIRFYFPHwycsgssrtyrygvsrgAEAPLLDDFVMSYLFAQWRHDFVHGWIKVPvthetQEECLGMAVLDMMRIA 190
Cdd:smart00295  73 TLyFRVKFYPPD-----------------PNQLKEDPTRLNLLYLQVRNDILEGRLPCP-----EEEALLLAALALQAEF 130

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907131829  191 KEKDQTPLAVYNSVSYKTFLPKCV---------RAKIQDYHiltrkriryrfrrfiQQFsqCKATARNLKLKYLINLETL 261
Cdd:smart00295 131 GDYDEELHDLRGELSLKRFLPKQLldsrklkewRERIVELH---------------KEL--IGLSPEEAKLKYLELARKL 193

                   ....*....
gi 1907131829  262 qSAFYTEQF 270
Cdd:smart00295 194 -PTYGVELF 201

FERM domain C-lobe of Non-receptor tyrosine-protein kinase TYK2; Tyk2 functions primarily in IL-12 and type I-IFN signaling as well as transduction of IL-23, IL-10, and IL-6 signals. A mutation in the Tyk2 gene has been associated with hyperimmunoglobulin E syndrome (HIES), a primary immunodeficiency characterized by elevated serum immunoglobulin E. Tyk2 has been shown to interact with FYN, PTPN6, IFNAR1, Ku80 and GNB2L1. JAK (also called Just Another Kinase) is a family of intracellular, non-receptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway. The JAK family in mammals consists of 4 members: JAK1, JAK2, JAK3 and TYK2. JAKs are composed of seven JAK homology (JH) domains (JH1-JH7) . The C-terminal JH1 domain is the main catalytic domain, followed by JH2, which is often referred to as a pseudokinase domain, followed by JH3-JH4 which is homologous to the SH2 domain, and lastly JH5-JH7 which is a FERM domain. Named after Janus, the two-faced Roman god of doorways, JAKs possess two near-identical phosphate-transferring domains; one which displays the kinase activity (JH1), while the other negatively regulates the kinase activity of the first (JH2). The FERM domain has a cloverleaf tripart structure composed of: (1) FERM_N (A-lobe or F1); (2) FERM_M (B-lobe, or F2); and (3) FERM_C (C-lobe or F3). The C-lobe/F3 within the FERM domain is part of the PH domain family. The FERM domain is found in the cytoskeletal-associated proteins such as ezrin, moesin, radixin, 4.1R, and merlin. These proteins provide a link between the membrane and cytoskeleton and are involved in signal transduction pathways. The FERM domain is also found in protein tyrosine phosphatases (PTPs), the tyrosine kinases FAK and JAK, in addition to other proteins involved in signaling. This domain is structurally similar to the PH and PTB domains and consequently is capable of binding to both peptides and phospholipids at different sites.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907131829 273 KESARGPSGEEIfatiIITGNGGIQW---------------------SRGKHKESETLT---EQDVQLYCDFPDIIDVSI 328
Cdd:cd13335    34 PEETINPPTHEV----MVSGTDGIQWrkvsaersqsdsysrhyfmkvMRQKSQKSEQPAlneEPKWVIFCDFQEITHIVI 109

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 1907131829 329 KQANqecsnesriVTVHKQDGKVLEIELSSLKEALSFVSLIDGYYRLTADAHHYLCKE 386
Cdd:cd13335   110 QGIN---------VCISRQDNKCMEISLPSSIQALSFVSLLDGYFRLTADSNHYLCHE 158

FERM domain C-lobe of Janus kinase 1; JAK1 is a tyrosine kinase protein essential in signaling type I and type II cytokines. It interacts with the gamma chain of type I cytokine receptors to elicit signals from the IL-2 receptor family, the IL-4 receptor family, the gp130 receptor family, ciliary neurotrophic factor receptor (CNTF-R), neurotrophin-1 receptor (NNT-1R) and Leptin-R). It also is involved in transducing a signal by type I (IFN-alpha/beta) and type II (IFN-gamma) interferons, and members of the IL-10 family via type II cytokine receptors. JAK (also called Just Another Kinase) is a family of intracellular, non-receptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway. The JAK family in mammals consists of 4 members: JAK1, JAK2, JAK3 and TYK2. JAKs are composed of seven JAK homology (JH) domains (JH1-JH7) . The C-terminal JH1 domain is the main catalytic domain, followed by JH2, which is often referred to as a pseudokinase domain, followed by JH3-JH4 which is homologous to the SH2 domain, and lastly JH5-JH7 which is a FERM domain. Named after Janus, the two-faced Roman god of doorways, JAKs possess two near-identical phosphate-transferring domains; one which displays the kinase activity (JH1), while the other negatively regulates the kinase activity of the first (JH2). The FERM domain has a cloverleaf tripart structure composed of: (1) FERM_N (A-lobe or F1); (2) FERM_M (B-lobe, or F2); and (3) FERM_C (C-lobe or F3). The C-lobe/F3 within the FERM domain is part of the PH domain family. The FERM domain is found in the cytoskeletal-associated proteins such as ezrin, moesin, radixin, 4.1R, and merlin. These proteins provide a link between the membrane and cytoskeleton and are involved in signal transduction pathways. The FERM domain is also found in protein tyrosine phosphatases (PTPs), the tyrosine kinases FAK and JAK, in addition to other proteins involved in signaling. This domain is structurally similar to the PH and PTB domains and consequently is capable of binding to both peptides and phospholipids at different sites.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907131829 288 IIITGNGGIQWSR-------------------GKHKESETLTEQDVQ--LYCDFPDIIDVSIKQAnqecsnesrIVTVHK 346
Cdd:cd13332    34 VSVTGNTGISWRRkpattavekkkkgkskknkLKGKKDEDKKKAREGwnNFSYFPEITHIVIKES---------TVTINR 104

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|
gi 1907131829 347 QDGKVLEIELSSLKEALSFVSLIDGYYRLTADAHHYLCKE 386
Cdd:cd13332   105 QDNKKMELKLSSRDEALSFAALVDGYFRLTADAHHYLCTD 144

Pseudokinase (repeat 1) domain of the Protein Tyrosine Kinases, Janus kinases; The Jak subfamily is composed of Jak1, Jak2, Jak3, TYK2, and similar proteins. They are cytoplasmic (or nonreceptor) PTKs containing an N-terminal FERM domain, followed by a Src homology 2 (SH2) domain, a pseudokinase domain, and a C-terminal catalytic tyr kinase domain. The pseudokinase domain shows similarity to tyr kinases but lacks crucial residues for catalytic activity and ATP binding. It modulates the kinase activity of the C-terminal catalytic domain. In the case of Jak2, the presumed pseudokinase (repeat 1) domain exhibits dual-specificity kinase activity, phosphorylating two negative regulatory sites in Jak2: Ser523 and Tyr570. Most Jaks are expressed in a wide variety of tissues, except for Jak3, which is expressed only in hematopoietic cells. Jaks are crucial for cytokine receptor signaling. They are activated by autophosphorylation upon cytokine-induced receptor aggregation, and subsequently trigger downstream signaling events such as the phosphorylation of signal transducers and activators of transcription (STATs). Jaks are also involved in regulating the surface expression of some cytokine receptors. The Jak-STAT pathway is involved in many biological processes including hematopoiesis, immunoregulation, host defense, fertility, lactation, growth, and embryogenesis. The Jak subfamily is part of a larger superfamily that includes the catalytic domains of other kinases such as serine/threonine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*...
gi 1907131829 545 LIFNESLGQGTFTKIFKGVRREVGDyGQLHKTEVLLKVLDKAHRNYSE 592
Cdd:cd05037     1 ITFHEHLGQGTFTNIYDGILREVGD-GRVQEVEVLLKVLDSDHRDISE 47

Src homology 2 (SH2) domain in Tyrosine Kinase 2 (Tyk2), a member of the Janus kinases (JAK); Tyk2 is a member of the tyrosine kinase and, more specifically, the Janus kinases (JAKs) protein families. This protein associates with the cytoplasmic domain of type I and type II cytokine receptors and promulgate cytokine signals by phosphorylating receptor subunits. It is also component of both the type I and type III interferon signaling pathways. As such, it may play a role in anti-viral immunity. A mutation in this gene has been associated with hyperimmunoglobulin E syndrome (HIES) - a primary immunodeficiency characterized by elevated serum immunoglobulin E. 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 1907131829 386 EVAPPAVLENIHSNCHGPISMDFAISKLKKAGNQTGLYVLRCSPKDFNKYFLTFAVERENV------IEYKHCLITKnEN 459
Cdd:cd10381     1 EVAPPRLVTSIQNGIHGPMMDPFVQAKLKKEWPEEGLYLIRWSTLDLHRLILAVAHRNPA*sngpggLRLRQFRIQQ-KG 79

                          90       100
                  ....*....|....*....|...
gi 1907131829 460 GEYNLSGTKRNFSNLKDLLNCYQ 482
Cdd:cd10381    80 SAFVLEGWGREFASVGDLRDALQ 102

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
                  ....*....|....*....|....*....|....*....|....
gi 1907131829 545 LIFNESLGQGTFTKIFKGVRRevgDYGQLHKTEVLLKVLDKAHR 588
Cdd:pfam07714   1 LTLGEKLGEGAFGEVYKGTLK---GEGENTKIKVAVKTLKEGAD 41