Conserved Protein Domain Family
PTK_Jak2_Jak3_rpt1

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cd05078: PTK_Jak2_Jak3_rpt1 (this model, PSSM-Id:133209 is obsolete and has been replaced by 270663)
Pseudokinase (repeat 1) domain of the Protein Tyrosine Kinases, Janus kinases 2 and 3
Protein Tyrosine Kinase (PTK) family; Janus kinase 2 (Jak2) and Jak3; pseudokinase domain (repeat 1). The PTKc (catalytic domain) family to which this subfamily belongs, is part of a larger superfamily that includes the catalytic domains of other kinases such as protein serine/threonine kinases, RIO kinases, and phosphoinositide 3-kinase (PI3K). PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. Jak2 and Jak3 are members of the Janus kinase (Jak) subfamily of proteins, which are cytoplasmic (or nonreceptor) tyr kinases 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. It modulates the kinase activity of the C-terminal catalytic domain. 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). Jak2 is widely expressed in many tissues while Jak3 is expressed only in hematopoietic cells. Jak2 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. Jak3 binds the shared receptor subunit common gamma chain and thus, is essential in the signaling of cytokines that use it such as IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. 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. Jak3 is important in lymphoid development and myeloid cell differentiation. Inactivating mutations in Jak3 have been reported in humans with severe combined immunodeficiency (SCID).
Statistics
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PSSM-Id: 133209
View PSSM: cd05078
Aligned: 6 rows
Threshold Bit Score: 498.218
Threshold Setting Gi: 45384524
Created: 19-Jun-2007
Updated: 17-Jan-2013
Structure
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Aligned Rows:
 
V617F mutation
Feature 1:V617F mutation site
Evidence:
  • Comment:The Jak2 V617F mutation is found in many myeloproliferative diseases. It is present in almost all patients with polycythemia vera, 50% of patients with essential thrombocytosis and myelofibrosis, and less commonly in chronic myelomonocytic leukemia (CMML), myelodysplasia, and acute myeloid leukemia.

Sequence Alignment
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Format: Row Display: Color Bits: Type Selection:
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
Feature 1                                                                            #           
gi 12643404  549 ESLGQGTFTKIFKGVRREvgdygqlheTEVLLKVLDKAHRnySESFFEAASMMSKLSHKHLVLNYGVCVcgdENILVQEF 628
gi 18858917  513 EGLGQGTFTQVFRGIRREvgdygevhkMEVVMKILDKSHRnyTESFFESASMMSQLSHKHLLLNYGICVcadEHIMVQEY 592
gi 49115290  542 ENLGQGTFTKIFKGKREElgdynkihvTEVLLKVLDKTHRsfSESFFEAASMMSQLSYKHLILNYGVCVcgdESILVQEY 621
gi 71896485  546 ESLGQGTFTKIFKGIRKEvgdygqlhqTEVLLKVLDKVHRnySESFFEAASMMSQLSYKHLVLNYGVCVcgeENILVQEY 625
gi 45384524  521 ESLGQGSFTHIYKGIKRDqkdd-efyqTPVVLKVMDSSHRncSESFLEAASIMSQLSHKHLVLLHGVSLg-kDSIMVQEY 598
gi 50403745  525 ENLGHGSFTKIYRGCRHEvvdg-earkTEVLLKVMDAKHKncMESFLEAASLMSQVSYRHLVLLHGVCMa-gDSTMVQEF 602
                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
Feature 1                                                                                        
gi 12643404  629 VKFGSLDTYLKKNkn--cINILWKLEVAKQLAWAMHFLEENTLIHGNVCAKNILLIREedrktgnpPFIKLSDPGISITV 706
gi 18858917  593 VRFGSLDTYLKRNrn--tINITWKLEVAKQLAWALHHLEEKSLTHGNVCARNVLVTREedrktgtpPFIKLSDPGISITV 670
gi 49115290  622 AKNGSLDTYLKRNkn--aINIMWKLEVSKQLAWAMHFLEDRNLVHGNVCSKNILLIREedrktgnpPFIKLSDPGISITV 699
gi 71896485  626 VKFGSLDTYLKKNkn--vINILWKLEVAKQLALAMHFLEDKGLVHGNVCAKNILLIREedrksgnlPFIKLSDPGISITV 703
gi 45384524  599 IRHGPLDLYLKKNhsegkVTTSWKLQVAKQLAYALNYLEDKKITHGNVSAKKVLLTREgdaassspPFIKLNDPGVSITV 678
gi 50403745  603 VHLGAIDMYLRKRgh--lVPASWKLQVVKQLAYALNYLEDKGLPHGNVSARKVLLAREgad--gspPFIKLSDPGVSPAV 678
                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
Feature 1                                                                                        
gi 12643404  707 lpkdILQERIPWVPPECIENpkNLNLATDKWSFGTTLWEICSGGDKPLSALDSQRKLQFYEDRHQLPAPKWAELANLINN 786
gi 18858917  671 qpreILLERIPWVPPECVKDsrNLSLAADKWSFGTTLWEIYCGGEQPLAAYDTAKKLLFYEDKHQLPAPKWTELASVINS 750
gi 49115290  700 lpkeILLERIPWVPPECIDNpkHLTLASDKWSFGTTLWEIYSGGDKPLNNLDSQRKSQFYEDRHQLPVPKWIELANLINS 779
gi 71896485  704 lprdILLERIPWVPPECIENprQLSLATDKWSFGTTLWEICSGGDKPLSALDSSRKLQFYEDRHQLPAPNWTELANLINN 783
gi 45384524  679 lakeWLVERIPWVAPECLSDpqSLALPADKWGFGATLWEIFSGGNMPVSLLEPQKKLQFYDSRLQLPAPRWSELAALIAQ 758
gi 50403745  679 lsleMLTDRIPWVAPECLREaqTLSLEADKWGFGATVWEVFSGVTMPISALDPAKKLQFYEDRQQLPAPKWTELALLIQQ 758
                        250       260
                 ....*....|....*....|
Feature 1                            
gi 12643404  787 CMDYePDFRPSFRAIIRDLN 806
gi 18858917  751 CMDYePLHRPSFRALIRDLN 770
gi 49115290  780 CMDYePDFRPSFRAIIRDLN 799
gi 71896485  784 CMDYePDFRPSFRAIIRDLN 803
gi 45384524  759 CIYA-PSRRPCFRAIIRDIN 777
gi 50403745  759 CMAYePVQRPSFRAVIRDLN 778

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