Catalytic domain of the Protein Tyrosine Kinase, Activated Cdc42-associated kinase; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. This subfamily includes Ack1, thirty-eight-negative kinase 1 (Tnk1), and similar proteins. They are cytoplasmic (or nonreceptor) PTKs containing an N-terminal catalytic domain, an SH3 domain, a Cdc42-binding CRIB domain, and a proline-rich region. They are mainly expressed in brain and skeletal tissues and are involved in the regulation of cell adhesion and growth, receptor degradation, and axonal guidance. Ack1 is also associated with androgen-independent prostate cancer progression. Tnk1 regulates TNFalpha signaling and may play an important role in cell death. The Ack-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        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720387340   1 MDDFIREVNAMHSLDHRNLIRLYGVVLTLPMKMVTELAPLGSLLDRLRKHQGHFLLGTLSRYAVQVAEGMAYLESKRFIH 80
Cdd:cd05040    42 MDDFLKEVNAMHSLDHPNLIRLYGVVLSSPLMMVTELAPLGSLLDRLRKDQGHFLISTLCDYAVQIANGMAYLESKRFIH 121

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720387340  81 RDLAARNLLLATRDLVKIGDFGLMRALPQNDDHYVMQEHRKVPFAWCAPESLKTRTFSHASDTWMFGVTLWEMFTYGQEP 160
Cdd:cd05040   122 RDLAARNILLASKDKVKIGDFGLMRALPQNEDHYVMQEHRKVPFAWCAPESLKTRKFSHASDVWMFGVTLWEMFTYGEEP 201

                         170       180       190       200       210
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 1720387340 161 WIGLNGSQILHKIDKEGERLPRPEDCPQDIYNVMVQCWAHKPEDRPTFVALRDFLLE 217
Cdd:cd05040   202 WLGLNGSQILEKIDKEGERLERPDDCPQDIYNVMLQCWAHKPADRPTFVALRDFLPE 258

EGFR receptor inhibitor Mig-6; When the kinase domain of EGFR binds to segment one of Mitogen induced gene 6 (Mig-6), EGFR becomes inactive due to the conformation it adopts which is Src/CDK like. The binding of the two proteins prevents EGFR acting as a cyclin-like activator for other kinase domains.The structure of Mig-6(1) consists of alpha helices-G and -H with a polar surface and hydrophobic residues for interactions with EGFR. A critical step for the activation of EGFR is the formation of an asymmetric dimer involving the kinase domains of the protein. Since Mig-6 binds to the kinase domain it blocks this process and EGFR becomes inactive.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1720387340 619 SPPRVPPREPLSPQGSRTPSPLVPPGSSP-------LPHRLSSSPGKTMPTTQSFASDPKYATPQVIQAPGPRA 685
Cdd:pfam11555   1 RPPQIPPRDPLSQPGSRTPSPMGLVVGSPqqpathsYSSYLSTSPGKLMPTTQSFASDPKYAAPKVIQAQGKDA 74

Variant SH3 domain;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1720387340 225 ALQDFE--EPDKLHIQMNDVITVIEgRAENYWWRGQNtrTLCVGPFPRNVVT 274
Cdd:pfam14604   1 ALYPYEpkDDDELSLQRGDVITVIE-ESEDGWWEGIN--TGRTGLVPANYVE 49

Catalytic domain of the Protein Tyrosine Kinase, Activated Cdc42-associated kinase; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. This subfamily includes Ack1, thirty-eight-negative kinase 1 (Tnk1), and similar proteins. They are cytoplasmic (or nonreceptor) PTKs containing an N-terminal catalytic domain, an SH3 domain, a Cdc42-binding CRIB domain, and a proline-rich region. They are mainly expressed in brain and skeletal tissues and are involved in the regulation of cell adhesion and growth, receptor degradation, and axonal guidance. Ack1 is also associated with androgen-independent prostate cancer progression. Tnk1 regulates TNFalpha signaling and may play an important role in cell death. The Ack-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        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720387340   1 MDDFIREVNAMHSLDHRNLIRLYGVVLTLPMKMVTELAPLGSLLDRLRKHQGHFLLGTLSRYAVQVAEGMAYLESKRFIH 80
Cdd:cd05040    42 MDDFLKEVNAMHSLDHPNLIRLYGVVLSSPLMMVTELAPLGSLLDRLRKDQGHFLISTLCDYAVQIANGMAYLESKRFIH 121

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720387340  81 RDLAARNLLLATRDLVKIGDFGLMRALPQNDDHYVMQEHRKVPFAWCAPESLKTRTFSHASDTWMFGVTLWEMFTYGQEP 160
Cdd:cd05040   122 RDLAARNILLASKDKVKIGDFGLMRALPQNEDHYVMQEHRKVPFAWCAPESLKTRKFSHASDVWMFGVTLWEMFTYGEEP 201

                         170       180       190       200       210
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 1720387340 161 WIGLNGSQILHKIDKEGERLPRPEDCPQDIYNVMVQCWAHKPEDRPTFVALRDFLLE 217
Cdd:cd05040   202 WLGLNGSQILEKIDKEGERLERPDDCPQDIYNVMLQCWAHKPADRPTFVALRDFLPE 258

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720387340   1 MDDFIREVNAMHSLDHRNLIRLYGVVL-TLPMKMVTELAPLGSLLDRLRKHQGHFLLGTLSRYAVQVAEGMAYLESKRFI 79
Cdd:pfam07714  45 REDFLEEASIMKKLDHPNIVKLLGVCTqGEPLYIVTEYMPGGDLLDFLRKHKRKLTLKDLLSMALQIAKGMEYLESKNFV 124

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720387340  80 HRDLAARNLLLATRDLVKIGDFGLMRALPqNDDHYVMQEHRKVPFAWCAPESLKTRTFSHASDTWMFGVTLWEMFTYGQE 159
Cdd:pfam07714 125 HRDLAARNCLVSENLVVKISDFGLSRDIY-DDDYYRKRGGGKLPIKWMAPESLKDGKFTSKSDVWSFGVLLWEIFTLGEQ 203

                         170       180       190       200       210
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1720387340 160 PWIGLNGSQILHKIdKEGERLPRPEDCPQDIYNVMVQCWAHKPEDRPTFVALRDFL 215
Cdd:pfam07714 204 PYPGMSNEEVLEFL-EDGYRLPQPENCPDELYDLMKQCWAYDPEDRPTFSELVEDL 258

EGFR receptor inhibitor Mig-6; When the kinase domain of EGFR binds to segment one of Mitogen induced gene 6 (Mig-6), EGFR becomes inactive due to the conformation it adopts which is Src/CDK like. The binding of the two proteins prevents EGFR acting as a cyclin-like activator for other kinase domains.The structure of Mig-6(1) consists of alpha helices-G and -H with a polar surface and hydrophobic residues for interactions with EGFR. A critical step for the activation of EGFR is the formation of an asymmetric dimer involving the kinase domains of the protein. Since Mig-6 binds to the kinase domain it blocks this process and EGFR becomes inactive.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1720387340 619 SPPRVPPREPLSPQGSRTPSPLVPPGSSP-------LPHRLSSSPGKTMPTTQSFASDPKYATPQVIQAPGPRA 685
Cdd:pfam11555   1 RPPQIPPRDPLSQPGSRTPSPMGLVVGSPqqpathsYSSYLSTSPGKLMPTTQSFASDPKYAAPKVIQAQGKDA 74

UBA domain found in non-receptor tyrosine-protein kinase TNK1 and similar proteins; TNK1, also called CD38 negative kinase 1, is a non-receptor protein tyrosine kinase (NRPTK) that has been implicated in the regulation of apoptosis, cell growth, nuclear factor-kappaB, and Ras. It associates with phospholipase C (PLC)-gamma1 and may play a role in phospholipid signal transduction. TNK1 contains an NH2-terminal kinase, a Src Homology 3 (SH3) domain, a proline-rich (PR) region, and a C-terminal ubiquitin-association (UBA) domain.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|
gi 1720387340 804 ADKVQMVEQLFGLGLRPRVECHKVLEMFDWNLEQAGCHLL 843
Cdd:cd14328     1 AVRYLKVEQLFRLGLASREECEKALERTNWNLELASSLLL 40

Variant SH3 domain;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1720387340 225 ALQDFE--EPDKLHIQMNDVITVIEgRAENYWWRGQNtrTLCVGPFPRNVVT 274
Cdd:pfam14604   1 ALYPYEpkDDDELSLQRGDVITVIE-ESEDGWWEGIN--TGRTGLVPANYVE 49

large tegument protein UL36; Provisional

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720387340  424 VPTPRPcAPSLAQLAMDACSLLDKTPPQS--------PTRALPRPLHPTPVVDWDARPLPPPPAYDDVAQDEDDFEVCSI 495
Cdd:PHA03247  2568 VPPPRP-APRPSEPAVTSRARRPDAPPQSarprapvdDRGDPRGPAPPSPLPPDTHAPDPPPPSPSPAANEPDPHPPPTV 2646

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720387340  496 NSTLVGAGLPAGP---------SQGETNYAFVPEQAQMPPALEDNLfLPPQGGGKPPSSVQTAEifqalqqecmrqlQVP 566
Cdd:PHA03247  2647 PPPERPRDDPAPGrvsrprrarRLGRAAQASSPPQRPRRRAARPTV-GSLTSLADPPPPPPTPE-------------PAP 2712

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720387340  567 TGQLTPSPTPGGDDKPQVPPRVPIPPRPTRPRVELSPAPSGEEETSRWPGPASPPR-VPPREPLSPQGSRTPSPLVPPGS 645
Cdd:PHA03247  2713 HALVSATPLPPGPAAARQASPALPAAPAPPAVPAGPATPGGPARPARPPTTAGPPApAPPAAPAAGPPRRLTRPAVASLS 2792

                          250       260       270       280       290       300       310       320
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720387340  646 SPLPHRLS-----------SSPGKTMPTTQSFASDPKYATPQVIQAPGPRAGPCILPIVRDG---------RKVSSTHYY 705
Cdd:PHA03247  2793 ESRESLPSpwdpadppaavLAPAAALPPAASPAGPLPPPTSAQPTAPPPPPGPPPPSLPLGGsvapggdvrRRPPSRSPA 2872

                          330       340       350       360       370       380       390       400
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720387340  706 LLPERPPYLeRYQRFLREAQSPEEPAALPVPPLLPPPSTPAPAAptatvRPMPQAAPDPKANFSTNNSNPGARPPSLRAT 785
Cdd:PHA03247  2873 AKPAAPARP-PVRRLARPAVSRSTESFALPPDQPERPPQPQAPP-----PPQPQPQPPPPPQPQPPPPPPPRPQPPLAPT 2946

                          410
                   ....*....|....*..
gi 1720387340  786 ARLPQRGCPGDGQEAAR 802
Cdd:PHA03247  2947 TDPAGAGEPSGAVPQPW 2963

Src homology 3 domain of Signal Transducing Adaptor Molecules; STAMs were discovered as proteins that are highly phosphorylated following cytokine and growth factor stimulation. They function in cytokine signaling and surface receptor degradation, as well as regulate Golgi morphology. They associate with many proteins including Jak2 and Jak3 tyrosine kinases, Hrs, AMSH, and UBPY. STAM adaptor proteins contain VHS (Vps27, Hrs, STAM homology), ubiquitin interacting (UIM), and SH3 domains. There are two vertebrate STAMs, STAM1 and STAM2, which may be functionally redundant; vertebrate STAMs contain ITAM motifs. They are part of the endosomal sorting complex required for transport (ESCRT-0). STAM2 deficiency in mice did not cause any obvious abnormality, while STAM1 deficiency resulted in growth retardation. Loss of both STAM1 and STAM2 in mice proved lethal, indicating that STAMs are important for embryonic development. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1720387340 222 DMRALQDFE--EPDKLHIQMNDVITVIEGRAENyWWRGQNTRTlcVGPFPRNVVTS 275
Cdd:cd11820     2 KVRALYDFEaaEDNELTFKAGEIITVLDDSDPN-WWKGSNHRG--EGLFPANFVTA 54

Catalytic domain of the Protein Tyrosine Kinase, Activated Cdc42-associated kinase; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. This subfamily includes Ack1, thirty-eight-negative kinase 1 (Tnk1), and similar proteins. They are cytoplasmic (or nonreceptor) PTKs containing an N-terminal catalytic domain, an SH3 domain, a Cdc42-binding CRIB domain, and a proline-rich region. They are mainly expressed in brain and skeletal tissues and are involved in the regulation of cell adhesion and growth, receptor degradation, and axonal guidance. Ack1 is also associated with androgen-independent prostate cancer progression. Tnk1 regulates TNFalpha signaling and may play an important role in cell death. The Ack-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        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720387340   1 MDDFIREVNAMHSLDHRNLIRLYGVVLTLPMKMVTELAPLGSLLDRLRKHQGHFLLGTLSRYAVQVAEGMAYLESKRFIH 80
Cdd:cd05040    42 MDDFLKEVNAMHSLDHPNLIRLYGVVLSSPLMMVTELAPLGSLLDRLRKDQGHFLISTLCDYAVQIANGMAYLESKRFIH 121

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720387340  81 RDLAARNLLLATRDLVKIGDFGLMRALPQNDDHYVMQEHRKVPFAWCAPESLKTRTFSHASDTWMFGVTLWEMFTYGQEP 160
Cdd:cd05040   122 RDLAARNILLASKDKVKIGDFGLMRALPQNEDHYVMQEHRKVPFAWCAPESLKTRKFSHASDVWMFGVTLWEMFTYGEEP 201

                         170       180       190       200       210
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 1720387340 161 WIGLNGSQILHKIDKEGERLPRPEDCPQDIYNVMVQCWAHKPEDRPTFVALRDFLLE 217
Cdd:cd05040   202 WLGLNGSQILEKIDKEGERLERPDDCPQDIYNVMLQCWAHKPADRPTFVALRDFLPE 258

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720387340    1 MDDFIREVNAMHSLDHRNLIRLYGVVLT-LPMKMVTELAPLGSLLDRLRKHQGHFLLGTLSRYAVQVAEGMAYLESKRFI 79
Cdd:smart00219  45 IEEFLREARIMRKLDHPNVVKLLGVCTEeEPLYIVMEYMEGGDLLSYLRKNRPKLSLSDLLSFALQIARGMEYLESKNFI 124

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720387340   80 HRDLAARNLLLATRDLVKIGDFGLMRALPqnDDHYVMQEHRKVPFAWCAPESLKTRTFSHASDTWMFGVTLWEMFTYGQE 159
Cdd:smart00219 125 HRDLAARNCLVGENLVVKISDFGLSRDLY--DDDYYRKRGGKLPIRWMAPESLKEGKFTSKSDVWSFGVLLWEIFTLGEQ 202

                          170       180       190       200       210
                   ....*....|....*....|....*....|....*....|....*....|....*.
gi 1720387340  160 PWIGLNGSQILHKIdKEGERLPRPEDCPQDIYNVMVQCWAHKPEDRPTFVALRDFL 215
Cdd:smart00219 203 PYPGMSNEEVLEYL-KNGYRLPQPPNCPPELYDLMLQCWAEDPEDRPTFSELVEIL 257

Catalytic domain of Protein Tyrosine Kinases; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. They can be classified into receptor and non-receptor tyr kinases. PTKs play important roles in many cellular processes including, lymphocyte activation, epithelium growth and maintenance, metabolism control, organogenesis regulation, survival, proliferation, differentiation, migration, adhesion, motility, and morphogenesis. Receptor tyr kinases (RTKs) are integral membrane proteins which contain an extracellular ligand-binding region, a transmembrane segment, 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, leading to intracellular signaling. Some RTKs are orphan receptors with no known ligands. Non-receptor (or cytoplasmic) tyr kinases are distributed in different intracellular compartments and are usually multi-domain proteins containing a catalytic tyr kinase domain as well as various regulatory domains such as SH3 and SH2. PTKs are usually autoinhibited and require a mechanism for activation. In many PTKs, the phosphorylation of tyr residues in the activation loop is essential for optimal activity. Aberrant expression of PTKs is associated with many development abnormalities and cancers.The PTK family is part of a larger superfamily that includes the catalytic domains of serine/threonine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720387340   1 MDDFIREVNAMHSLDHRNLIRLYGVVLT-LPMKMVTELAPLGSLLDRLRKHQGHF---LLGTLS-----RYAVQVAEGMA 71
Cdd:cd00192    40 RKDFLKEARVMKKLGHPNVVRLLGVCTEeEPLYLVMEYMEGGDLLDFLRKSRPVFpspEPSTLSlkdllSFAIQIAKGME 119

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720387340  72 YLESKRFIHRDLAARNLLLATRDLVKIGDFGLMRALPqNDDHYVMQEHRKVPFAWCAPESLKTRTFSHASDTWMFGVTLW 151
Cdd:cd00192   120 YLASKKFVHRDLAARNCLVGEDLVVKISDFGLSRDIY-DDDYYRKKTGGKLPIRWMAPESLKDGIFTSKSDVWSFGVLLW 198

                         170       180       190       200       210       220
                  ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1720387340 152 EMFTYGQEPWIGLNGSQILHKIdKEGERLPRPEDCPQDIYNVMVQCWAHKPEDRPTFVALRDFL 215
Cdd:cd00192   199 EIFTLGATPYPGLSNEEVLEYL-RKGYRLPKPENCPDELYELMLSCWQLDPEDRPTFSELVERL 261

Catalytic domain of Src kinase-like Protein Tyrosine Kinases; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. Src subfamily members include Src, Lck, Hck, Blk, Lyn, Fgr, Fyn, Yrk, and Yes. Src (or c-Src) proteins are cytoplasmic (or non-receptor) PTKs which are anchored to the plasma membrane. They 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). Src proteins are involved in signaling pathways that regulate cytokine and growth factor responses, cytoskeleton dynamics, cell proliferation, survival, and differentiation. They were identified as the first proto-oncogene products, and they regulate cell adhesion, invasion, and motility in cancer cells and tumor vasculature, contributing to cancer progression and metastasis. Src kinases are overexpressed in a variety of human cancers, making them attractive targets for therapy. They are also implicated in acute inflammatory responses and osteoclast function. Src, Fyn, Yes, and Yrk are widely expressed, while Blk, Lck, Hck, Fgr, and Lyn show a limited expression pattern. The Src-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        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720387340   2 DDFIREVNAMHSLDHRNLIRLYGVVLTL-PMKMVTELAPLGSLLDRLRKHQGHFL-LGTLSRYAVQVAEGMAYLESKRFI 79
Cdd:cd05034    35 EAFLQEAQIMKKLRHDKLVQLYAVCSDEePIYIVTELMSKGSLLDYLRTGEGRALrLPQLIDMAAQIASGMAYLESRNYI 114

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720387340  80 HRDLAARNLLLATRDLVKIGDFGLMRALpqNDDHYVMQEHRKVPFAWCAPESLKTRTFSHASDTWMFGVTLWEMFTYGQE 159
Cdd:cd05034   115 HRDLAARNILVGENNVCKVADFGLARLI--EDDEYTAREGAKFPIKWTAPEAALYGRFTIKSDVWSFGILLYEIVTYGRV 192

                         170       180       190       200       210
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1720387340 160 PWIGLNGSQILHKIDKeGERLPRPEDCPQDIYNVMVQCWAHKPEDRPTFVALRDFL 215
Cdd:cd05034   193 PYPGMTNREVLEQVER-GYRMPKPPGCPDELYDIMLQCWKKEPEERPTFEYLQSFL 247

Catalytic domain of Epidermal Growth Factor Receptor-like Protein Tyrosine Kinases; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. EGFR (HER, ErbB) subfamily members include EGFR (HER1, ErbB1), HER2 (ErbB2), HER3 (ErbB3), HER4 (ErbB4), and similar proteins. They are receptor PTKs (RTKs) containing an extracellular EGF-related ligand-binding region, a transmembrane helix, and a cytoplasmic region with a tyr kinase domain and a regulatory C-terminal tail. Unlike other PTKs, phosphorylation of the activation loop of EGFR proteins is not critical to their activation. Instead, they are activated by ligand-induced dimerization, resulting in the phosphorylation of tyr residues in the C-terminal tail, which serve as binding sites for downstream signaling molecules. Collectively, they can recognize a variety of ligands including EGF, TGFalpha, and neuregulins, among others. All four subfamily members can form homo- or heterodimers. HER3 contains an impaired kinase domain and depends on its heterodimerization partner for activation. EGFR subfamily members are involved in signaling pathways leading to a broad range of cellular responses including cell proliferation, differentiation, migration, growth inhibition, and apoptosis. Gain of function alterations, through their overexpression, deletions, or point mutations in their kinase domains, have been implicated in various cancers. These receptors are targets of many small molecule inhibitors and monoclonal antibodies used in cancer therapy. The EGFR 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        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720387340   3 DFIREVNAMHSLDHRNLIRLYGVVLTLPMKMVTELAPLGSLLDRLRKHQGHFLLGTLSRYAVQVAEGMAYLESKRFIHRD 82
Cdd:cd05057    55 EILDEAYVMASVDHPHLVRLLGICLSSQVQLITQLMPLGCLLDYVRNHRDNIGSQLLLNWCVQIAKGMSYLEEKRLVHRD 134

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720387340  83 LAARNLLLATRDLVKIGDFGLMRALPQNDDHYVMQEHrKVPFAWCAPESLKTRTFSHASDTWMFGVTLWEMFTYGQEPWI 162
Cdd:cd05057   135 LAARNVLVKTPNHVKITDFGLAKLLDVDEKEYHAEGG-KVPIKWMALESIQYRIYTHKSDVWSYGVTVWELMTFGAKPYE 213

                         170       180       190       200
                  ....*....|....*....|....*....|....*....|....*....
gi 1720387340 163 GLNGSQILHKIDKeGERLPRPEDCPQDIYNVMVQCWAHKPEDRPTFVAL 211
Cdd:cd05057   214 GIPAVEIPDLLEK-GERLPQPPICTIDVYMVLVKCWMIDAESRPTFKEL 261

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        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720387340   2 DDFIREVNAMHSLDHRNLIRLYGV-VLTLPMKMVTELAPLGSLLDRLRKHQGHFLLGTLSRYAVQVAEGMAYLESKRFIH 80
Cdd:cd05068    48 EDFLREAQIMKKLRHPKLIQLYAVcTLEEPIYIITELMKHGSLLEYLQGKGRSLQLPQLIDMAAQVASGMAYLESQNYIH 127

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720387340  81 RDLAARNLLLATRDLVKIGDFGLMRALpQNDDHYVMQEHRKVPFAWCAPESLKTRTFSHASDTWMFGVTLWEMFTYGQEP 160
Cdd:cd05068   128 RDLAARNVLVGENNICKVADFGLARVI-KVEDEYEAREGAKFPIKWTAPEAANYNRFSIKSDVWSFGILLTEIVTYGRIP 206

                         170       180       190       200       210
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1720387340 161 WIGLNGSQILHKIDKeGERLPRPEDCPQDIYNVMVQCWAHKPEDRPTFVALR 212
Cdd:cd05068   207 YPGMTNAEVLQQVER-GYRMPCPPNCPPQLYDIMLECWKADPMERPTFETLQ 257

Catalytic domain of the Protein Tyrosine Kinases, Src-related kinase lacking C-terminal regulatory tyrosine and N-terminal myristylation sites (Srm) and Breast tumor kinase (Brk); PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. Srm and Brk (also called protein tyrosine kinase 6) are members of the Src subfamily of proteins, which are cytoplasmic (or non-receptor) PTKs. Brk has been found to be overexpressed in a majority of breast tumors. Src kinases in general 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). Srm and Brk however, lack the N-terminal myristylation sites. Src proteins are involved in signaling pathways that regulate cytokine and growth factor responses, cytoskeleton dynamics, cell proliferation, survival, and differentiation. The Srm/Brk 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        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720387340   2 DDFIREVNAMHSLDHRNLIRLYGVV-LTLPMKMVTELAPLGSLLDRLRKHQGHFL-LGTLSRYAVQVAEGMAYLESKRFI 79
Cdd:cd05148    47 QDFQKEVQALKRLRHKHLISLFAVCsVGEPVYIITELMEKGSLLAFLRSPEGQVLpVASLIDMACQVAEGMAYLEEQNSI 126

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720387340  80 HRDLAARNLLLATRDLVKIGDFGLMRALpqNDDHYVMQEHrKVPFAWCAPESLKTRTFSHASDTWMFGVTLWEMFTYGQE 159
Cdd:cd05148   127 HRDLAARNILVGEDLVCKVADFGLARLI--KEDVYLSSDK-KIPYKWTAPEAASHGTFSTKSDVWSFGILLYEMFTYGQV 203

                         170       180       190       200       210
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1720387340 160 PWIGLNGSQILHKIDkEGERLPRPEDCPQDIYNVMVQCWAHKPEDRPTFVALRDFL 215
Cdd:cd05148   204 PYPGMNNHEVYDQIT-AGYRMPCPAKCPQEIYKIMLECWAAEPEDRPSFKALREEL 258

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720387340   2 DDFIREVNAMHSLDHRNLIRLYGVVLTLPMKMVTELAPLGSLLDRLRKHQGHFL-LGTLSRYAVQVAEGMAYLESKRFIH 80
Cdd:cd05067    47 DAFLAEANLMKQLQHQRLVRLYAVVTQEPIYIITEYMENGSLVDFLKTPSGIKLtINKLLDMAAQIAEGMAFIEERNYIH 126

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720387340  81 RDLAARNLLLATRDLVKIGDFGLMRALPQNDdhYVMQEHRKVPFAWCAPESLKTRTFSHASDTWMFGVTLWEMFTYGQEP 160
Cdd:cd05067   127 RDLRAANILVSDTLSCKIADFGLARLIEDNE--YTAREGAKFPIKWTAPEAINYGTFTIKSDVWSFGILLTEIVTHGRIP 204

                         170       180       190       200       210
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 1720387340 161 WIGLNGSQILHKIDKeGERLPRPEDCPQDIYNVMVQCWAHKPEDRPTFVALRDFL 215
Cdd:cd05067   205 YPGMTNPEVIQNLER-GYRMPRPDNCPEELYQLMRLCWKERPEDRPTFEYLRSVL 258

Catalytic domain of the Protein Tyrosine Kinase, Spleen tyrosine kinase; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. Syk is a cytoplasmic (or nonreceptor) PTK containing two Src homology 2 (SH2) domains N-terminal to the catalytic tyr kinase domain. Syk was first cloned from the spleen, and its function in hematopoietic cells is well-established. It is involved in the signaling downstream of activated receptors (including B-cell and Fc receptors) that contain ITAMs (immunoreceptor tyr activation motifs), leading to processes such as cell proliferation, differentiation, survival, adhesion, migration, and phagocytosis. More recently, Syk expression has been detected in other cell types (including epithelial cells, vascular endothelial cells, neurons, hepatocytes, and melanocytes), suggesting a variety of biological functions in non-immune cells. Syk plays a critical role in maintaining vascular integrity and in wound healing during embryogenesis. It also regulates Vav3, which is important in osteoclast function including bone development. In breast epithelial cells, where Syk acts as a negative regulator for EGFR signaling, loss of Syk expression is associated with abnormal proliferation during cancer development suggesting a potential role as a tumor suppressor. In mice, Syk has been shown to inhibit malignant transformation of mammary epithelial cells induced with murine mammary tumor virus (MMTV). The Syk 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        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720387340   2 DDFIREVNAMHSLDHRNLIRLYGVVLTLPMKMVTELAPLGSLLDRLRKHQgHFLLGTLSRYAVQVAEGMAYLESKRFIHR 81
Cdd:cd05116    41 DELLREANVMQQLDNPYIVRMIGICEAESWMLVMEMAELGPLNKFLQKNR-HVTEKNITELVHQVSMGMKYLEESNFVHR 119

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720387340  82 DLAARNLLLATRDLVKIGDFGLMRALPQNDDHYVMQEHRKVPFAWCAPESLKTRTFSHASDTWMFGVTLWEMFTYGQEPW 161
Cdd:cd05116   120 DLAARNVLLVTQHYAKISDFGLSKALRADENYYKAQTHGKWPVKWYAPECMNYYKFSSKSDVWSFGVLMWEAFSYGQKPY 199

                         170       180       190       200       210
                  ....*....|....*....|....*....|....*....|....*....|
gi 1720387340 162 IGLNGSQILHKIDKeGERLPRPEDCPQDIYNVMVQCWAHKPEDRPTFVAL 211
Cdd:cd05116   200 KGMKGNEVTQMIEK-GERMECPAGCPPEMYDLMKLCWTYDVDERPGFAAV 248