FERM domain C-lobe of Focal Adhesion Kinase 1 and 2; FAK1 (also called FRNK/Focal adhesion kinase-related nonkinase; p125FAK/pp125FAK;PTK2/Protein-tyrosine kinase 2 protein tyrosine kinase 2 (PTK2) is a non-receptor tyrosine kinase that localizes to focal adhesions in adherent cells. It has been implicated in diverse cellular roles including cell locomotion, mitogen response and cell survival. The N-terminal region of FAK1 contains a FERM domain, a linker, a kinase domain, and a C-terminal FRNK (FAK-related-non-kinase) domain. Three subdomains of FERM: (1) FERM_N (A-lobe or F1); (2) FERM_M (B-lobe, or F2); and (3) FERM_C (C-lobe or F3), form a cloverleaf fold, similar to those of known FERM structures despite the low sequence conservation. The C-lobe/F3 within the FERM domain is part of the PH domain family. The phosphoinositide-binding site found in ERM family proteins is not present in the FERM domain of FAK1. The adjacent Src SH3 and SH2 binding sites in the linker of FAK1 associates with the F3 and F1 lobes and are thought to be involved in regulation. The FERM domain of FAK1 can inhibit enzymatic activity and repress FAK signaling. In an inactive state of FAK1, the FERM domain is thought to interact with the catalytic domain of FAK1 to repress its activity. Upon activation this interaction is disrupted and its kinase activity restored. The FRNK domain is thought to function as a negative regulator of kinase activity. The C-lobe/F3 is the third structural domain within the FERM domain. 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 1208915010 254 DKECFKCALGSSWIISVELAIGPEEGISYLTDKGCNPTHLADFTQVQTIQYSNSEDKDRKGMLQLKIAGAPEPLTVTAPS 333
Cdd:cd13190     1 DQEIFKCALGSGWSIPVDLVIGPEVGISYLTDKGSAPTHLADFEQIQSIQTSKSEDKDGKALLQLKIAGASEPLSITCSS 80

                          90       100       110
                  ....*....|....*....|....*....|.
gi 1208915010 334 LTIAENMADLIDGYCRLVNGTSQSFIIRPQK 364
Cdd:cd13190    81 LATAESLADLIDGYCRLVNQTDSSLIIRPEK 111

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 1208915010   36 VLKVFHYFESNSEpttwasiIRHGDATDVRGIIQKIVDSHKVKHVACYGFRLSHLRSEEVHWLHVDMGVSSVREKyelah 115
Cdd:smart00295   1 VLKVYLLDGTTLE-------FEVDSSTTAEELLETVCRKLGIRESEYFGLQFEDPDEDLRHWLDPAKTLLDQDVK----- 68

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1208915010  116 pPEEWKYELRIRYLPKgFLNQFTEDKPTLNFFYQQVKSDYMLEIAdQVDQEIALKLGCLEIRRSYWEMRGNALEkksnye 195
Cdd:smart00295  69 -SEPLTLYFRVKFYPP-DPNQLKEDPTRLNLLYLQVRNDILEGRL-PCPEEEALLLAALALQAEFGDYDEELHD------ 139

                          170       180       190       200       210       220
                   ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1208915010  196 vLEKDVGLKRFFPKSLLDSVKAKTLRKLIQQTFRQFANLNREESILKFFEILSPVYRFDKECF 258
Cdd:smart00295 140 -LRGELSLKRFLPKQLLDSRKLKEWRERIVELHKELIGLSPEEAKLKYLELARKLPTYGVELF 201

FERM domain C-lobe of Focal Adhesion Kinase 1 and 2; FAK1 (also called FRNK/Focal adhesion kinase-related nonkinase; p125FAK/pp125FAK;PTK2/Protein-tyrosine kinase 2 protein tyrosine kinase 2 (PTK2) is a non-receptor tyrosine kinase that localizes to focal adhesions in adherent cells. It has been implicated in diverse cellular roles including cell locomotion, mitogen response and cell survival. The N-terminal region of FAK1 contains a FERM domain, a linker, a kinase domain, and a C-terminal FRNK (FAK-related-non-kinase) domain. Three subdomains of FERM: (1) FERM_N (A-lobe or F1); (2) FERM_M (B-lobe, or F2); and (3) FERM_C (C-lobe or F3), form a cloverleaf fold, similar to those of known FERM structures despite the low sequence conservation. The C-lobe/F3 within the FERM domain is part of the PH domain family. The phosphoinositide-binding site found in ERM family proteins is not present in the FERM domain of FAK1. The adjacent Src SH3 and SH2 binding sites in the linker of FAK1 associates with the F3 and F1 lobes and are thought to be involved in regulation. The FERM domain of FAK1 can inhibit enzymatic activity and repress FAK signaling. In an inactive state of FAK1, the FERM domain is thought to interact with the catalytic domain of FAK1 to repress its activity. Upon activation this interaction is disrupted and its kinase activity restored. The FRNK domain is thought to function as a negative regulator of kinase activity. The C-lobe/F3 is the third structural domain within the FERM domain. 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 1208915010 254 DKECFKCALGSSWIISVELAIGPEEGISYLTDKGCNPTHLADFTQVQTIQYSNSEDKDRKGMLQLKIAGAPEPLTVTAPS 333
Cdd:cd13190     1 DQEIFKCALGSGWSIPVDLVIGPEVGISYLTDKGSAPTHLADFEQIQSIQTSKSEDKDGKALLQLKIAGASEPLSITCSS 80

                          90       100       110
                  ....*....|....*....|....*....|.
gi 1208915010 334 LTIAENMADLIDGYCRLVNGTSQSFIIRPQK 364
Cdd:cd13190    81 LATAESLADLIDGYCRLVNQTDSSLIIRPEK 111

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 1208915010   36 VLKVFHYFESNSEpttwasiIRHGDATDVRGIIQKIVDSHKVKHVACYGFRLSHLRSEEVHWLHVDMGVSSVREKyelah 115
Cdd:smart00295   1 VLKVYLLDGTTLE-------FEVDSSTTAEELLETVCRKLGIRESEYFGLQFEDPDEDLRHWLDPAKTLLDQDVK----- 68

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1208915010  116 pPEEWKYELRIRYLPKgFLNQFTEDKPTLNFFYQQVKSDYMLEIAdQVDQEIALKLGCLEIRRSYWEMRGNALEkksnye 195
Cdd:smart00295  69 -SEPLTLYFRVKFYPP-DPNQLKEDPTRLNLLYLQVRNDILEGRL-PCPEEEALLLAALALQAEFGDYDEELHD------ 139

                          170       180       190       200       210       220
                   ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1208915010  196 vLEKDVGLKRFFPKSLLDSVKAKTLRKLIQQTFRQFANLNREESILKFFEILSPVYRFDKECF 258
Cdd:smart00295 140 -LRGELSLKRFLPKQLLDSRKLKEWRERIVELHKELIGLSPEEAKLKYLELARKLPTYGVELF 201

FERM domain B-lobe; The FERM domain has a cloverleaf tripart structure (FERM_N, FERM_M, FERM_C/N, alpha-, and C-lobe/A-lobe, B-lobe, C-lobe/F1, F2, F3). 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, the tyrosine kinases FAK and JAK, in addition to other proteins involved in signaling. This domain is structurally similar to the pleckstrin homology (PH) and phosphotyrosine binding (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 1208915010 143 TLNFFYQQVKSDYMLEIAdQVDQEIALKLGCLEIRRSYwemrGNalekKSNYEVLEKDVGLKRFFPKSLLDSVKAKTLRK 222
Cdd:cd14473     1 TRYLLYLQVKRDILEGRL-PCSEETAALLAALALQAEY----GD----YDPSEHKPKYLSLKRFLPKQLLKQRKPEEWEK 71

                          90       100
                  ....*....|....*....|....*.
gi 1208915010 223 LIQQTFRQFANLNREESILKFFEILS 248
Cdd:cd14473    72 RIVELHKKLRGLSPAEAKLKYLKIAR 97

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
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1208915010 435 IELGRCIGEGQFGDVHQGIY-MSPENPALAVAIKTCKNCTSDSVREKFLQEACL 487
Cdd:pfam07714   1 LTLGEKLGEGAFGEVYKGTLkGEGENTKIKVAVKTLKEGADEEEREDFLEEASI 54

FERM domain C-lobe of Focal Adhesion Kinase 1 and 2; FAK1 (also called FRNK/Focal adhesion kinase-related nonkinase; p125FAK/pp125FAK;PTK2/Protein-tyrosine kinase 2 protein tyrosine kinase 2 (PTK2) is a non-receptor tyrosine kinase that localizes to focal adhesions in adherent cells. It has been implicated in diverse cellular roles including cell locomotion, mitogen response and cell survival. The N-terminal region of FAK1 contains a FERM domain, a linker, a kinase domain, and a C-terminal FRNK (FAK-related-non-kinase) domain. Three subdomains of FERM: (1) FERM_N (A-lobe or F1); (2) FERM_M (B-lobe, or F2); and (3) FERM_C (C-lobe or F3), form a cloverleaf fold, similar to those of known FERM structures despite the low sequence conservation. The C-lobe/F3 within the FERM domain is part of the PH domain family. The phosphoinositide-binding site found in ERM family proteins is not present in the FERM domain of FAK1. The adjacent Src SH3 and SH2 binding sites in the linker of FAK1 associates with the F3 and F1 lobes and are thought to be involved in regulation. The FERM domain of FAK1 can inhibit enzymatic activity and repress FAK signaling. In an inactive state of FAK1, the FERM domain is thought to interact with the catalytic domain of FAK1 to repress its activity. Upon activation this interaction is disrupted and its kinase activity restored. The FRNK domain is thought to function as a negative regulator of kinase activity. The C-lobe/F3 is the third structural domain within the FERM domain. 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 1208915010 254 DKECFKCALGSSWIISVELAIGPEEGISYLTDKGCNPTHLADFTQVQTIQYSNSEDKDRKGMLQLKIAGAPEPLTVTAPS 333
Cdd:cd13190     1 DQEIFKCALGSGWSIPVDLVIGPEVGISYLTDKGSAPTHLADFEQIQSIQTSKSEDKDGKALLQLKIAGASEPLSITCSS 80

                          90       100       110
                  ....*....|....*....|....*....|.
gi 1208915010 334 LTIAENMADLIDGYCRLVNGTSQSFIIRPQK 364
Cdd:cd13190    81 LATAESLADLIDGYCRLVNQTDSSLIIRPEK 111

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 1208915010   36 VLKVFHYFESNSEpttwasiIRHGDATDVRGIIQKIVDSHKVKHVACYGFRLSHLRSEEVHWLHVDMGVSSVREKyelah 115
Cdd:smart00295   1 VLKVYLLDGTTLE-------FEVDSSTTAEELLETVCRKLGIRESEYFGLQFEDPDEDLRHWLDPAKTLLDQDVK----- 68

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1208915010  116 pPEEWKYELRIRYLPKgFLNQFTEDKPTLNFFYQQVKSDYMLEIAdQVDQEIALKLGCLEIRRSYWEMRGNALEkksnye 195
Cdd:smart00295  69 -SEPLTLYFRVKFYPP-DPNQLKEDPTRLNLLYLQVRNDILEGRL-PCPEEEALLLAALALQAEFGDYDEELHD------ 139

                          170       180       190       200       210       220
                   ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1208915010  196 vLEKDVGLKRFFPKSLLDSVKAKTLRKLIQQTFRQFANLNREESILKFFEILSPVYRFDKECF 258
Cdd:smart00295 140 -LRGELSLKRFLPKQLLDSRKLKEWRERIVELHKELIGLSPEEAKLKYLELARKLPTYGVELF 201

FERM domain B-lobe; The FERM domain has a cloverleaf tripart structure (FERM_N, FERM_M, FERM_C/N, alpha-, and C-lobe/A-lobe, B-lobe, C-lobe/F1, F2, F3). 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, the tyrosine kinases FAK and JAK, in addition to other proteins involved in signaling. This domain is structurally similar to the pleckstrin homology (PH) and phosphotyrosine binding (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 1208915010 143 TLNFFYQQVKSDYMLEIAdQVDQEIALKLGCLEIRRSYwemrGNalekKSNYEVLEKDVGLKRFFPKSLLDSVKAKTLRK 222
Cdd:cd14473     1 TRYLLYLQVKRDILEGRL-PCSEETAALLAALALQAEY----GD----YDPSEHKPKYLSLKRFLPKQLLKQRKPEEWEK 71

                          90       100
                  ....*....|....*....|....*.
gi 1208915010 223 LIQQTFRQFANLNREESILKFFEILS 248
Cdd:cd14473    72 RIVELHKKLRGLSPAEAKLKYLKIAR 97

FERM central domain; This domain is the central structural domain of the FERM domain.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1208915010 143 TLNFFYQQVKSDYMLEIADqVDQEIALKLGCLEIRRSYwemrGNALEKKSNYEVLekdvGLKRFFPKSLLDSVKAKTLRK 222
Cdd:pfam00373  11 TRHLLYLQAKDDILEGRLP-CSEEEALLLAALQLQAEF----GDYQPSSHTSEYL----SLESFLPKQLLRKMKSKELEK 81

                          90       100
                  ....*....|....*....|....*.
gi 1208915010 223 LIQQTFRQFANLNREESILKFFEILS 248
Cdd:pfam00373  82 RVLEAHKNLRGLSAEEAKLKYLQIAQ 107

Tyrosine kinase, catalytic domain; Phosphotransferases. Tyrosine-specific kinase subfamily.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....
gi 1208915010  435 IELGRCIGEGQFGDVHQGIY-MSPENPALAVAIKTCKNCTSDSVREKFLQEACL 487
Cdd:smart00219   1 LTLGKKLGEGAFGEVYKGKLkGKGGKKKVEVAVKTLKEDASEQQIEEFLREARI 54

Protein kinase; unclassified specificity; Phosphotransferases. The specificity of this class of kinases can not be predicted. Possible dual-specificity Ser/Thr/Tyr kinase.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....
gi 1208915010  435 IELGRCIGEGQFGDVHQGIY-MSPENPALAVAIKTCKNCTSDSVREKFLQEACL 487
Cdd:smart00221   1 LTLGKKLGEGAFGEVYKGTLkGKGDGKEVEVAVKTLKEDASEQQIEEFLREARI 54

Catalytic domain of Fyn-related kinase-like Protein Tyrosine Kinases; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. Frk and Srk are members of the Src subfamily of proteins, which are cytoplasmic (or non-receptor) PTKs. Frk, also known as Rak, is specifically expressed in liver, lung, kidney, intestine, mammary glands, and the islets of Langerhans. Rodent homologs were previously referred to as GTK (gastrointestinal tyr kinase), BSK (beta-cell Src-like kinase), or IYK (intestinal tyr kinase). Studies in mice reveal that Frk is not essential for viability. It plays a role in the signaling that leads to cytokine-induced beta-cell death in Type I diabetes. It also regulates beta-cell number during embryogenesis and early in life. Src kinases contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr. They are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). The Frk-like 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        50
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 1208915010 428 YEIQRERIELGRCIGEGQFGDVHQGIYmspeNPALAVAIKTCKNCTSDSvrEKFLQEA 485
Cdd:cd05068     3 WEIDRKSLKLLRKLGSGQFGEVWEGLW----NNTTPVAVKTLKPGTMDP--EDFLREA 54

Catalytic domain of Spleen Tyrosine Kinase-like Protein Tyrosine Kinases; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. The Syk-like subfamily is composed of Syk, ZAP-70, Shark, and similar proteins. They are cytoplasmic (or nonreceptor) PTKs containing two Src homology 2 (SH2) domains N-terminal to the catalytic tyr kinase domain. They are involved in the signaling downstream of activated receptors (including B-cell, T-cell, and Fc receptors) that contain ITAMs (immunoreceptor tyr activation motifs), leading to processes such as cell proliferation, differentiation, survival, adhesion, migration, and phagocytosis. Syk is important in B-cell receptor signaling, while Zap-70 is primarily expressed in T-cells and NK cells, and is a crucial component in T-cell receptor signaling. Syk also plays a central role in Fc receptor-mediated phagocytosis in the adaptive immune system. Shark is exclusively expressed in ectodermally derived epithelia, and is localized preferentially to the apical surface of the epithelial cells, it may play a role in a signaling pathway for epithelial cell polarity. The Syk-like subfamily is part of a larger superfamily that includes the catalytic domains of other kinases such as protein serine/threonine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*
gi 1208915010 441 IGEGQFGDVHQGIYMSPENPALAVAIKTCKNCTSDSVREKFLQEA 485
Cdd:cd05060     3 LGHGNFGSVRKGVYLMKSGKEVEVAVKTLKQEHEKAGKKEFLREA 47

Catalytic domain of Fes-like Protein Tyrosine Kinases; Protein Tyrosine Kinase (PTK) family; Fes subfamily; catalytic (c) domain. Fes subfamily members include Fes (or Fps), Fer, and similar proteins. The PTKc family 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. Fes subfamily proteins are cytoplasmic (or nonreceptor) tyr kinases containing an N-terminal region with FCH (Fes/Fer/CIP4 homology) and coiled-coil domains, followed by a SH2 domain, and a C-terminal catalytic domain. The genes for Fes (feline sarcoma) and Fps (Fujinami poultry sarcoma) were first isolated from tumor-causing retroviruses. The viral oncogenes encode chimeric Fes proteins consisting of Gag sequences at the N-termini, resulting in unregulated tyr kinase activity. Fes and Fer kinases play roles in haematopoiesis, inflammation and immunity, growth factor signaling, cytoskeletal regulation, cell migration and adhesion, and the regulation of cell-cell interactions. Fes and Fer show redundancy in their biological functions.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*
gi 1208915010 441 IGEGQFGDVHQGIYMSPEnpaLAVAIKTCKNCTSDSVREKFLQEA 485
Cdd:cd05041     3 IGRGNFGDVYRGVLKPDN---TEVAVKTCRETLPPDLKRKFLQEA 44

Catalytic domain of C-terminal Src kinase-like Protein Tyrosine Kinases; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. This subfamily is composed of Csk, Chk, and similar proteins. They are cytoplasmic (or nonreceptor) PTKs containing the Src homology domains, SH3 and SH2, N-terminal to the catalytic tyr kinase domain. They negatively regulate the activity of Src kinases that are anchored to the plasma membrane. To inhibit Src kinases, Csk and Chk are translocated to the membrane via binding to specific transmembrane proteins, G-proteins, or adaptor proteins near the membrane. Csk catalyzes the tyr phosphorylation of the regulatory C-terminal tail of Src kinases, resulting in their inactivation. Chk inhibit Src kinases using a noncatalytic mechanism by simply binding to them. As negative regulators of Src kinases, Csk and Chk play important roles in cell proliferation, survival, and differentiation, and consequently, in cancer development and progression. The Csk-like subfamily is part of a larger superfamily that includes the catalytic domains of other kinases such as protein serine/threonine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 1208915010 428 YEIQRERIELGRCIGEGQFGDVHQGIYMSPEnpalaVAIKTCKNctSDSVREKFLQEA 485
Cdd:cd05039     1 WAINKKDLKLGELIGKGEFGDVMLGDYRGQK-----VAVKCLKD--DSTAAQAFLAEA 51

Catalytic domain of the Protein Tyrosine Kinases, Tropomyosin Related Kinases; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. The Trk subfamily consists of TrkA, TrkB, TrkC, and similar proteins. They are receptor PTKs (RTKs) containing an extracellular region with arrays of leucine-rich motifs flanked by two cysteine-rich clusters followed by two immunoglobulin-like domains, a transmembrane segment, and an intracellular catalytic domain. Binding to their ligands, the nerve growth factor (NGF) family of neutrotrophins, leads to Trk receptor oligomerization and activation of the catalytic domain. Trk receptors are mainly expressed in the peripheral and central nervous systems. They play important roles in cell fate determination, neuronal survival and differentiation, as well as in the regulation of synaptic plasticity. Altered expression of Trk receptors is associated with many human diseases. The Trk subfamily is part of a larger superfamily that includes the catalytic domains of other kinases such as protein serine/threonine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1208915010 429 EIQRERIELGRCIGEGQFGDVHQG--IYMSPENPALAVAIKTCKNCTSDSVREKFLQEACLKLPGDKDHV 496
Cdd:cd05049     1 HIKRDTIVLKRELGEGAFGKVFLGecYNLEPEQDKMLVAVKTLKDASSPDARKDFEREAELLTNLQHENI 70

Catalytic domain of the Protein Tyrosine Kinase, Tyro3; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. Tyro3 (or Sky) is predominantly expressed in the central nervous system and the brain, and functions as a neurotrophic factor. It is also expressed in osteoclasts and has a role in bone resorption. Tyro3 is a member of the TAM subfamily, composed of receptor PTKs (RTKs) containing an extracellular ligand-binding region with two immunoglobulin-like domains followed by two fibronectin type III repeats, a transmembrane segment, and an intracellular catalytic domain. Binding to their ligands, Gas6 and protein S, leads to receptor dimerization, autophosphorylation, activation, and intracellular signaling. The Tyro3 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        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1208915010 426 RDYEIQRERIELGRCIGEGQFGDVHQGIYMSPENPALAVAIKTCK---NCTSDSvrEKFLQEACLKLPGDKDHVC 497
Cdd:cd05074     2 KDVLIQEQQFTLGRMLGKGEFGSVREAQLKSEDGSFQKVAVKMLKadiFSSSDI--EEFLREAACMKEFDHPNVI 74

FERM domain C-lobe of FERM and PDZ domain containing proteins 1, 3, and 4 (FRMPD1, 3, 4); The function of FRMPD1, FRMPD3, and FRMPD4 is unknown at present. These proteins contain an N-terminal PDZ (post synaptic density protein (PSD95), Drosophila disc large tumor suppressor (Dlg1), and zonula occludens-1 protein (zo-1) domain and a C-terminal FERM domain. PDZ (also known as DHR (Dlg homologous region) or GLGF (glycine-leucine-glycine-phenylalanine) domains) help anchor transmembrane proteins to the cytoskeleton and hold together signaling complexes. PDZ domains bind to a short region of the C-terminus of other specific proteins. The FERM domain is composed of three subdomains: (1) FERM_N (A-lobe or F1); (2) FERM_M (B-lobe, or F2); and (3) FERM_C (C-lobe or F3), which form a clover leaf fold. 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 1208915010 270 VELAIGPEEGISYLTDKGCNPTH-LADFTQVQTIQYSNSEDKDRKGMLQLKIAgapEPLTVTAPSLTiAENMADLIDGYC 348
Cdd:cd13183    18 VTLLVGPRYGISHVINHKLNLLAlLAEFSHISRIELLRESDKVSRVELHIHDV---KPITLLMESPD-AKDLACLIAGYY 93

                  ..
gi 1208915010 349 RL 350
Cdd:cd13183    94 RL 95

Catalytic domain of the Protein Tyrosine Kinase, Lyn; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. Lyn is a member of the Src subfamily of proteins, which are cytoplasmic (or non-receptor) PTKs. Lyn is expressed in B lymphocytes and myeloid cells. It exhibits both positive and negative regulatory roles in B cell receptor (BCR) signaling. Lyn, as well as Fyn and Blk, promotes B cell activation by phosphorylating ITAMs (immunoreceptor tyr activation motifs) in CD19 and in Ig components of BCR. It negatively regulates signaling by its unique ability to phosphorylate ITIMs (immunoreceptor tyr inhibition motifs) in cell surface receptors like CD22 and CD5. Lyn also plays an important role in G-CSF receptor signaling by phosphorylating a variety of adaptor molecules. Src kinases contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr. They are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). The Lyn 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        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1208915010 428 YEIQRERIELGRCIGEGQFGDVHQGIYmspeNPALAVAIKTCKNCTSdSVrEKFLQEACL 487
Cdd:cd05072     2 WEIPRESIKLVKKLGAGQFGEVWMGYY----NNSTKVAVKTLKPGTM-SV-QAFLEEANL 55

Catalytic domain of the Protein Tyrosine Kinases, Class EphA Ephrin Receptors; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. This subfamily is composed of most class EphA receptors including EphA3, EphA4, EphA5, and EphA7, but excluding EphA1, EphA2 and EphA10. Class EphA receptors bind GPI-anchored ephrin-A ligands. There are ten vertebrate EphA receptors (EphA1-10), which display promiscuous interactions with six ephrin-A ligands. One exception is EphA4, which also binds ephrins-B2/B3. EphA receptors and ephrin-A ligands are expressed in multiple areas of the developing brain, especially in the retina and tectum. They are part of a system controlling retinotectal mapping. EphRs comprise the largest subfamily of receptor PTKs (RTKs). EphRs contain an ephrin-binding domain and two fibronectin repeats extracellularly, a transmembrane segment, and a cytoplasmic tyr kinase domain. Binding of the ephrin ligand to EphR requires cell-cell contact since both are anchored to the plasma membrane. The resulting downstream signals occur bidirectionally in both EphR-expressing cells (forward signaling) and ephrin-expressing cells (reverse signaling). Ephrin/EphR interaction mainly results in cell-cell repulsion or adhesion, making it important in neural development and plasticity, cell morphogenesis, cell-fate determination, embryonic development, tissue patterning, and angiogenesis. The EphA 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        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1208915010 430 IQRERIELGRCIGEGQFGDVHQGIYMSPENPALAVAIKTCKNCTSDSVREKFLQEACLKlpGDKDH 495
Cdd:cd05066     1 IDASCIKIEKVIGAGEFGEVCSGRLKLPGKREIPVAIKTLKAGYTEKQRRDFLSEASIM--GQFDH 64

Catalytic domain of the Protein Tyrosine Kinases, Lymphocyte-specific kinase and Blk; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. Lck and Blk are members of the Src subfamily of proteins, which are cytoplasmic (or non-receptor) PTKs. Lck is expressed in T-cells and natural killer cells. It plays a critical role in T-cell maturation, activation, and T-cell receptor (TCR) signaling. Lck phosphorylates ITAM (immunoreceptor tyr activation motif) sequences on several subunits of TCRs, leading to the activation of different second messenger cascades. Phosphorylated ITAMs serve as binding sites for other signaling factor such as Syk and ZAP-70, leading to their activation and propagation of downstream events. In addition, Lck regulates drug-induced apoptosis by interfering with the mitochondrial death pathway. The apototic role of Lck is independent of its primary function in T-cell signaling. Blk is expressed specifically in B-cells. It is involved in pre-BCR (B-cell receptor) signaling. Src kinases contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr. They are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). The Lck/Blk 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.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1208915010 427 DYEIQRERIELGRCIGEGQFGDVHQGIYmspeNPALAVAIKTCKNCTSDSvrEKFLQEACL 487
Cdd:cd05067     1 EWEVPRETLKLVERLGAGQFGEVWMGYY----NGHTKVAIKSLKQGSMSP--DAFLAEANL 55

Catalytic domain of the Protein Tyrosine Kinase, Insulin-like Growth Factor-1 Receptor; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. IGF-1R is a receptor PTK (RTK) that is composed of two alphabeta heterodimers. Binding of the ligand (IGF-1 or IGF-2) to the extracellular alpha subunit activates the intracellular tyr kinase domain of the transmembrane beta subunit. Receptor activation leads to autophosphorylation, which stimulates downstream kinase activities and biological function. IGF-1R signaling is important in the differentiation, growth, and survival of normal cells. In cancer cells, where it is frequently overexpressed, IGF-1R is implicated in proliferation, the suppression of apoptosis, invasion, and metastasis. IGF-1R is being developed as a therapeutic target in cancer treatment. The IGF-1R 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        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1208915010 428 YEIQRERIELGRCIGEGQFGDVHQGIY--MSPENPALAVAIKTCKNCTSDSVREKFLQEA 485
Cdd:cd05062     1 WEVAREKITMSRELGQGSFGMVYEGIAkgVVKDEPETRVAIKTVNEAASMRERIEFLNEA 60

Catalytic domain of the Protein Tyrosine Kinase, Insulin Receptor; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. InsR is a receptor PTK (RTK) that is composed of two alphabeta heterodimers. Binding of the insulin ligand to the extracellular alpha subunit activates the intracellular tyr kinase domain of the transmembrane beta subunit. Receptor activation leads to autophosphorylation, stimulating downstream kinase activities, which initiate signaling cascades and biological function. InsR signaling plays an important role in many cellular processes including glucose homeostasis, glycogen synthesis, lipid and protein metabolism, ion and amino acid transport, cell cycle and proliferation, cell differentiation, gene transcription, and nitric oxide synthesis. Insulin resistance, caused by abnormalities in InsR signaling, has been described in diabetes, hypertension, cardiovascular disease, metabolic syndrome, heart failure, and female infertility. The InsR 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        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1208915010 428 YEIQRERIELGRCIGEGQFGDVHQGIY--MSPENPALAVAIKTCKNCTSDSVREKFLQEA 485
Cdd:cd05061     1 WEVSREKITLLRELGQGSFGMVYEGNArdIIKGEAETRVAVKTVNESASLRERIEFLNEA 60

Catalytic domain of the Protein Tyrosine Kinase, C-ros; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. This subfamily contains c-ros, Sevenless, and similar proteins. The proto-oncogene c-ros encodes an orphan receptor PTK (RTK) with an unknown ligand. RTKs contain an extracellular ligand-binding domain, a transmembrane region, and an intracellular tyr kinase domain. RTKs are usually activated through ligand binding, which causes dimerization and autophosphorylation of the intracellular tyr kinase catalytic domain. C-ros is expressed in embryonic cells of the kidney, intestine and lung, but disappears soon after birth. It persists only in the adult epididymis. Male mice bearing inactive mutations of c-ros lack the initial segment of the epididymis and are infertile. The Drosophila protein, Sevenless, is required for the specification of the R7 photoreceptor cell during eye development. The c-ros subfamily is part of a larger superfamily that includes the catalytic domains of other kinases such as protein serine/threonine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1208915010 441 IGEGQFGDVHQGI---YMSPENPALAVAIKTCKNCTSDSVREKFLQEAclKLPGDkdhvcFAHHSILSVL 507
Cdd:cd05044     3 LGSGAFGEVFEGTakdILGDGSGETKVAVKTLRKGATDQEKAEFLKEA--HLMSN-----FKHPNILKLL 65

Catalytic domain of the Protein Tyrosine Kinase, Hematopoietic cell kinase; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. Hck is a member of the Src subfamily of proteins, which are cytoplasmic (or non-receptor) PTKs. Hck is present in myeloid and lymphoid cells that play a role in the development of cancer. It may be important in the oncogenic signaling of the protein Tel-Abl, which induces a chronic myelogenous leukemia (CML)-like disease. Hck also acts as a negative regulator of G-CSF-induced proliferation of granulocytic precursors, suggesting a possible role in the development of acute myeloid leukemia (AML). In addition, Hck is essential in regulating the degranulation of polymorphonuclear leukocytes. Genetic polymorphisms affect the expression level of Hck, which affects PMN mediator release and influences the development of chronic obstructive pulmonary disease (COPD). Src kinases contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr. They are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). The Hck 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        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1208915010 424 EARDYEIQRERIELGRCIGEGQFGDVhqgiYMSPENPALAVAIKTCKNCTSdSVrEKFLQEACL 487
Cdd:cd05073     2 EKDAWEIPRESLKLEKKLGAGQFGEV----WMATYNKHTKVAVKTMKPGSM-SV-EAFLAEANV 59

Catalytic domain of the Protein Tyrosine Kinase, Tropomyosin Related Kinase A; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. TrkA is a receptor PTK (RTK) containing an extracellular region with arrays of leucine-rich motifs flanked by two cysteine-rich clusters followed by two immunoglobulin-like domains, a transmembrane segment, and an intracellular catalytic domain. Binding of TrkA to its ligand, nerve growth factor (NGF), results in receptor oligomerization and activation of the catalytic domain. TrkA is expressed mainly in neural-crest-derived sensory and sympathetic neurons of the peripheral nervous system, and in basal forebrain cholinergic neurons of the central nervous system. It is critical for neuronal growth, differentiation and survival. Alternative TrkA splicing has been implicated as a pivotal regulator of neuroblastoma (NB) behavior. Normal TrkA expression is associated with better NB prognosis, while the hypoxia-regulated TrkAIII splice variant promotes NB pathogenesis and progression. Aberrant TrkA expression has also been demonstrated in non-neural tumors including prostate, breast, lung, and pancreatic cancers. The TrkA subfamily is part of a larger superfamily that includes the catalytic domains of other kinases such as protein serine/threonine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1208915010 430 IQRERIELGRCIGEGQFGDVH--QGIYMSPENPALAVAIKTCKNCTsDSVREKFLQEACL 487
Cdd:cd05092     2 IKRRDIVLKWELGEGAFGKVFlaECHNLLPEQDKMLVAVKALKEAT-ESARQDFQREAEL 60

Catalytic domain of the Protein Tyrosine Kinases, Platelet Derived Growth Factor Receptors; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. The PDGFR subfamily consists of PDGFR alpha, PDGFR beta, KIT, CSF-1R, the mammalian FLT3, and similar proteins. They are receptor PTKs (RTKs) containing an extracellular ligand-binding region with five immunoglobulin-like domains, a transmembrane segment, and an intracellular catalytic domain. PDGFR kinase domains are autoinhibited by their juxtamembrane regions containing tyr residues. The binding to their ligands leads to receptor dimerization, trans phosphorylation and activation, and intracellular signaling. PDGFR subfamily receptors are important in the development of a variety of cells. PDGFRs are expressed in a many cells including fibroblasts, neurons, endometrial cells, mammary epithelial cells, and vascular smooth muscle cells. PDGFR signaling is critical in normal embryonic development, angiogenesis, and wound healing. Kit is important in the development of melanocytes, germ cells, mast cells, hematopoietic stem cells, the interstitial cells of Cajal, and the pacemaker cells of the GI tract. CSF-1R signaling is critical in the regulation of macrophages and osteoclasts. Mammalian FLT3 plays an important role in the survival, proliferation, and differentiation of stem cells. The PDGFR subfamily is part of a larger superfamily that includes the catalytic domains of other kinases such as protein serine/threonine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase .

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 1208915010 428 YEIQRERIELGRCIGEGQFGDVHQGIY--MSPENPALAVAIKTCKNCTSDSVREKFLQE 484
Cdd:cd05055    30 WEFPRNNLSFGKTLGAGAFGKVVEATAygLSKSDAVMKVAVKMLKPTAHSSEREALMSE 88

Catalytic domain of the Protein Tyrosine Kinase, Tropomyosin Related Kinase B; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. TrkB is a receptor PTK (RTK) containing an extracellular region with arrays of leucine-rich motifs flanked by two cysteine-rich clusters followed by two immunoglobulin-like domains, a transmembrane segment, and an intracellular catalytic domain. Binding of TrkB to its ligands, brain-derived neurotrophic factor (BDNF) or neurotrophin 4 (NT4), results in receptor oligomerization and activation of the catalytic domain. TrkB is broadly expressed in the nervous system and in some non-neural tissues. It plays important roles in cell proliferation, differentiation, and survival. BDNF/Trk signaling plays a key role in regulating activity-dependent synaptic plasticity. TrkB also contributes to protection against gp120-induced neuronal cell death. TrkB overexpression is associated with poor prognosis in neuroblastoma (NB) and other human cancers. It acts as a suppressor of anoikis (detachment-induced apoptosis) and contributes to tumor metastasis. The TrkB subfamily is part of a larger superfamily that includes the catalytic domains of other kinases such as protein serine/threonine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1208915010 430 IQRERIELGRCIGEGQFGDVH--QGIYMSPENPALAVAIKTCKNcTSDSVREKFLQEACLKLPGDKDHV 496
Cdd:cd05093     2 IKRHNIVLKRELGEGAFGKVFlaECYNLCPEQDKILVAVKTLKD-ASDNARKDFHREAELLTNLQHEHI 69