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        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907067260 710 LRILKETELKRVKVLGSGAFGTVYKGIWVPEGETVKIPVAIKILNETTGPKANVEFMDEALIMASMDHPHLVRLLGVCLS 789
Cdd:cd05110     1 LRILKETELKRVKVLGSGAFGTVYKGIWVPEGETVKIPVAIKILNETTGPKANVEFMDEALIMASMDHPHLVRLLGVCLS 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*
gi 1907067260 790 PTIQLVTQLMPHGCLLDYVHEHKDNIGSQLLLNWCVQIAKGMMYL 834
Cdd:cd05110    81 PTIQLVTQLMPHGCLLDYVHEHKDNIGSQLLLNWCVQIAKGMMYL 125

Furin-like cysteine rich region;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907067260 186 CGRCHKSCT-GRCWGPteNHCQTltrtVCAEQCDGRCYGPyvSDCCHRECAGGCSGPKDTDCFACMNFNDSGACVTQCPQ 264
Cdd:pfam00757  12 MEKCHSCCNnGYCWGP--GHCQK----VCPEQCKKRCTKP--GECCHEQCLGGCTGPNDSDCLACRHFNDEGTCVDQCPP 83

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1907067260 265 tfvynpttfqlehnfnAKYTYGAFCV--KKCP-------HNFVVDSSSCVRACPSSKMEVeENGIKMCKPCTDICPK 332
Cdd:pfam00757  84 ----------------GTYQFGWRCVtfKECPkshlpgyNPLVIHNGECVRECPSGYTEV-ENNSRKCEPCEGLCPK 143

Receptor L domain; The L domains from these receptors make up the bilobal ligand binding site. Each L domain consists of a single-stranded right hand beta-helix. This Pfam entry is missing the first 50 amino acid residues of the domain.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907067260 358 NCTKINGNLIFLVTGIHGDPYNaidaidpekLNVFRTVREITGFLNIQSWppNMTDFSVFSNLVTIGGRVLY-SGLSLLI 436
Cdd:pfam01030   1 NCTVIYGNLEITLIDENNDSEL---------LSFLSNVEEITGYLLIANT--NLVSLSFLPNLRIIRGRNLFdDNYALYI 69

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|...
gi 1907067260 437 LKQQGITSLQFQSLKEISAGNIYITDNSNLCYYHT-INWTTLF 478
Cdd:pfam01030  70 LDNPNLTELGLPSLKEITSGGVYIHNNPKLCYTETeILWKLLL 112

Catalytic domain of the Protein Tyrosine Kinase, HER4; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. HER4 (ErbB4) is a member of the EGFR (HER, ErbB) subfamily of proteins, which 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, leading to the phosphorylation of tyr residues in the C-terminal tail, which serve as binding sites for downstream signaling molecules. Ligands that bind HER4 fall into two groups, the neuregulins (or heregulins) and some EGFR (HER1) ligands including betacellulin, HBEGF, and epiregulin. All four neuregulins (NRG1-4) interact with HER4. Upon ligand binding, HER4 forms homo- or heterodimers with other HER proteins. HER4 is essential in embryonic development. It is implicated in mammary gland, cardiac, and neural development. As a postsynaptic receptor of NRG1, HER4 plays an important role in synaptic plasticity and maturation. The impairment of NRG1/HER4 signaling may contribute to schizophrenia. The HER4 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 1907067260 710 LRILKETELKRVKVLGSGAFGTVYKGIWVPEGETVKIPVAIKILNETTGPKANVEFMDEALIMASMDHPHLVRLLGVCLS 789
Cdd:cd05110     1 LRILKETELKRVKVLGSGAFGTVYKGIWVPEGETVKIPVAIKILNETTGPKANVEFMDEALIMASMDHPHLVRLLGVCLS 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*
gi 1907067260 790 PTIQLVTQLMPHGCLLDYVHEHKDNIGSQLLLNWCVQIAKGMMYL 834
Cdd:cd05110    81 PTIQLVTQLMPHGCLLDYVHEHKDNIGSQLLLNWCVQIAKGMMYL 125

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 1907067260 718 LKRVKVLGSGAFGTVYKGIWVPEGETVKIPVAIKILNETTGPKANVEFMDEALIMASMDHPHLVRLLGVCL-SPTIQLVT 796
Cdd:pfam07714   1 LTLGEKLGEGAFGEVYKGTLKGEGENTKIKVAVKTLKEGADEEEREDFLEEASIMKKLDHPNIVKLLGVCTqGEPLYIVT 80

                          90       100       110
                  ....*....|....*....|....*....|....*...
gi 1907067260 797 QLMPHGCLLDYVHEHKDNIGSQLLLNWCVQIAKGMMYL 834
Cdd:pfam07714  81 EYMPGGDLLDFLRKHKRKLTLKDLLSMALQIAKGMEYL 118

Furin-like cysteine rich region;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907067260 186 CGRCHKSCT-GRCWGPteNHCQTltrtVCAEQCDGRCYGPyvSDCCHRECAGGCSGPKDTDCFACMNFNDSGACVTQCPQ 264
Cdd:pfam00757  12 MEKCHSCCNnGYCWGP--GHCQK----VCPEQCKKRCTKP--GECCHEQCLGGCTGPNDSDCLACRHFNDEGTCVDQCPP 83

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1907067260 265 tfvynpttfqlehnfnAKYTYGAFCV--KKCP-------HNFVVDSSSCVRACPSSKMEVeENGIKMCKPCTDICPK 332
Cdd:pfam00757  84 ----------------GTYQFGWRCVtfKECPkshlpgyNPLVIHNGECVRECPSGYTEV-ENNSRKCEPCEGLCPK 143

Receptor L domain; The L domains from these receptors make up the bilobal ligand binding site. Each L domain consists of a single-stranded right hand beta-helix. This Pfam entry is missing the first 50 amino acid residues of the domain.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907067260 358 NCTKINGNLIFLVTGIHGDPYNaidaidpekLNVFRTVREITGFLNIQSWppNMTDFSVFSNLVTIGGRVLY-SGLSLLI 436
Cdd:pfam01030   1 NCTVIYGNLEITLIDENNDSEL---------LSFLSNVEEITGYLLIANT--NLVSLSFLPNLRIIRGRNLFdDNYALYI 69

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|...
gi 1907067260 437 LKQQGITSLQFQSLKEISAGNIYITDNSNLCYYHT-INWTTLF 478
Cdd:pfam01030  70 LDNPNLTELGLPSLKEITSGGVYIHNNPKLCYTETeILWKLLL 112

Serine/threonine protein kinase [Signal transduction mechanisms];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907067260 721 VKVLGSGAFGTVYKGIWVPEGEtvkiPVAIKILNE--TTGPKANVEFMDEALIMASMDHPHLVRLLGV-CLSPTIQLVTQ 797
Cdd:COG0515    12 LRLLGRGGMGVVYLARDLRLGR----PVALKVLRPelAADPEARERFRREARALARLNHPNIVRVYDVgEEDGRPYLVME 87

                          90       100       110
                  ....*....|....*....|....*....|....*..
gi 1907067260 798 LMPHGCLLDYVHEHKdNIGSQLLLNWCVQIAKGMMYL 834
Cdd:COG0515    88 YVEGESLADLLRRRG-PLPPAEALRILAQLAEALAAA 123

Furin-like repeats. Cysteine rich region. Exact function of the domain is not known. Furin is a serine-kinase dependent proprotein processor. Other members of this family include endoproteases and cell surface receptors.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*...
gi 1907067260 229 CCHRECAGgCSGPKDTDCFACMNFN--DSGACVTQCPQTFVYNPTTFQ 274
Cdd:cd00064     1 PCHPSCAT-CTGPGPDQCTSCRHGFylDGGTCVSECPEGTYADTEGGV 47

Furin-like repeats;

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|
gi 1907067260  229 CCHRECAGgCSGPKDTDCFACMNFN--DSGACVTQCPQTF 266
Cdd:smart00261   6 PCHPECAT-CTGPGPDDCTSCKHGFflDGGKCVSECPPGT 44

Catalytic domain of the Protein Tyrosine Kinase, HER4; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. HER4 (ErbB4) is a member of the EGFR (HER, ErbB) subfamily of proteins, which 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, leading to the phosphorylation of tyr residues in the C-terminal tail, which serve as binding sites for downstream signaling molecules. Ligands that bind HER4 fall into two groups, the neuregulins (or heregulins) and some EGFR (HER1) ligands including betacellulin, HBEGF, and epiregulin. All four neuregulins (NRG1-4) interact with HER4. Upon ligand binding, HER4 forms homo- or heterodimers with other HER proteins. HER4 is essential in embryonic development. It is implicated in mammary gland, cardiac, and neural development. As a postsynaptic receptor of NRG1, HER4 plays an important role in synaptic plasticity and maturation. The impairment of NRG1/HER4 signaling may contribute to schizophrenia. The HER4 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 1907067260 710 LRILKETELKRVKVLGSGAFGTVYKGIWVPEGETVKIPVAIKILNETTGPKANVEFMDEALIMASMDHPHLVRLLGVCLS 789
Cdd:cd05110     1 LRILKETELKRVKVLGSGAFGTVYKGIWVPEGETVKIPVAIKILNETTGPKANVEFMDEALIMASMDHPHLVRLLGVCLS 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*
gi 1907067260 790 PTIQLVTQLMPHGCLLDYVHEHKDNIGSQLLLNWCVQIAKGMMYL 834
Cdd:cd05110    81 PTIQLVTQLMPHGCLLDYVHEHKDNIGSQLLLNWCVQIAKGMMYL 125

Catalytic domain of the Protein Tyrosine Kinase, Epidermal Growth Factor Receptor; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. EGFR (HER1, ErbB1) is a receptor PTK (RTK) 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, leading to the phosphorylation of tyr residues in the C-terminal tail, which serve as binding sites for downstream signaling molecules. Ligands for EGFR include EGF, heparin binding EGF-like growth factor (HBEGF), epiregulin, amphiregulin, TGFalpha, and betacellulin. Upon ligand binding, EGFR can form homo- or heterodimers with other EGFR subfamily members. The EGFR signaling pathway is one of the most important pathways regulating cell proliferation, differentiation, survival, and growth. Overexpression and mutation in the kinase domain of EGFR have been implicated in the development and progression of a variety of cancers. A number of monoclonal antibodies and small molecule inhibitors have been developed that target EGFR, including the antibodies Cetuximab and Panitumumab, which are used in combination with other therapies for the treatment of colorectal cancer and non-small cell lung carcinoma (NSCLC). The small molecule inhibitors Gefitinib (Iressa) and Erlotinib (Tarceva), already used for NSCLC, are undergoing clinical trials for other types of cancer including gastrointestinal, breast, head and neck, and bladder. 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 1907067260 710 LRILKETELKRVKVLGSGAFGTVYKGIWVPEGETVKIPVAIKILNETTGPKANVEFMDEALIMASMDHPHLVRLLGVCLS 789
Cdd:cd05108     1 LRILKETEFKKIKVLGSGAFGTVYKGLWIPEGEKVKIPVAIKELREATSPKANKEILDEAYVMASVDNPHVCRLLGICLT 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*
gi 1907067260 790 PTIQLVTQLMPHGCLLDYVHEHKDNIGSQLLLNWCVQIAKGMMYL 834
Cdd:cd05108    81 STVQLITQLMPFGCLLDYVREHKDNIGSQYLLNWCVQIAKGMNYL 125

Catalytic domain of the Protein Tyrosine Kinase, HER2; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. HER2 (ErbB2, HER2/neu) is a member of the EGFR (HER, ErbB) subfamily of proteins, which 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, leading to the phosphorylation of tyr residues in the C-terminal tail, which serve as binding sites for downstream signaling molecules. HER2 does not bind to any known EGFR subfamily ligands, but contributes to the kinase activity of all possible heterodimers. It acts as the preferred partner of other ligand-bound EGFR proteins and functions as a signal amplifier, with the HER2-HER3 heterodimer being the most potent pair in mitogenic signaling. HER2 plays an important role in cell development, proliferation, survival and motility. Overexpression of HER2 results in its activation and downstream signaling, even in the absence of ligand. HER2 overexpression, mainly due to gene amplification, has been shown in a variety of human cancers. Its role in breast cancer is especially well-documented. HER2 is up-regulated in about 25% of breast tumors and is associated with increases in tumor aggressiveness, recurrence and mortality. HER2 is a target for monoclonal antibodies and small molecule inhibitors, which are being developed as treatments for cancer. The first humanized antibody approved for clinical use is Trastuzumab (Herceptin), which is being used in combination with other therapies to improve the survival rates of patients with HER2-overexpressing breast cancer. The HER2 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 1907067260 710 LRILKETELKRVKVLGSGAFGTVYKGIWVPEGETVKIPVAIKILNETTGPKANVEFMDEALIMASMDHPHLVRLLGVCLS 789
Cdd:cd05109     1 MRILKETELKKVKVLGSGAFGTVYKGIWIPDGENVKIPVAIKVLRENTSPKANKEILDEAYVMAGVGSPYVCRLLGICLT 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*
gi 1907067260 790 PTIQLVTQLMPHGCLLDYVHEHKDNIGSQLLLNWCVQIAKGMMYL 834
Cdd:cd05109    81 STVQLVTQLMPYGCLLDYVRENKDRIGSQDLLNWCVQIAKGMSYL 125

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 1907067260 718 LKRVKVLGSGAFGTVYKGIWVPEGETVKIPVAIKILNETTGPKANVEFMDEALIMASMDHPHLVRLLGVCL-SPTIQLVT 796
Cdd:pfam07714   1 LTLGEKLGEGAFGEVYKGTLKGEGENTKIKVAVKTLKEGADEEEREDFLEEASIMKKLDHPNIVKLLGVCTqGEPLYIVT 80

                          90       100       110
                  ....*....|....*....|....*....|....*...
gi 1907067260 797 QLMPHGCLLDYVHEHKDNIGSQLLLNWCVQIAKGMMYL 834
Cdd:pfam07714  81 EYMPGGDLLDFLRKHKRKLTLKDLLSMALQIAKGMEYL 118

Furin-like cysteine rich region;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907067260 186 CGRCHKSCT-GRCWGPteNHCQTltrtVCAEQCDGRCYGPyvSDCCHRECAGGCSGPKDTDCFACMNFNDSGACVTQCPQ 264
Cdd:pfam00757  12 MEKCHSCCNnGYCWGP--GHCQK----VCPEQCKKRCTKP--GECCHEQCLGGCTGPNDSDCLACRHFNDEGTCVDQCPP 83

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1907067260 265 tfvynpttfqlehnfnAKYTYGAFCV--KKCP-------HNFVVDSSSCVRACPSSKMEVeENGIKMCKPCTDICPK 332
Cdd:pfam00757  84 ----------------GTYQFGWRCVtfKECPkshlpgyNPLVIHNGECVRECPSGYTEV-ENNSRKCEPCEGLCPK 143

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 1907067260 722 KVLGSGAFGTVYKGIWVPEGETvKIPVAIKILNETTGPKANVEFMDEALIMASMDHPHLVRLLGVCLSP-TIQLVTQLMP 800
Cdd:cd00192     1 KKLGEGAFGEVYKGKLKGGDGK-TVDVAVKTLKEDASESERKDFLKEARVMKKLGHPNVVRLLGVCTEEePLYLVMEYME 79

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|..
gi 1907067260 801 HGCLLDYVHEHK--------DNIGSQLLLNWCVQIAKGMMYL 834
Cdd:cd00192    80 GGDLLDFLRKSRpvfpspepSTLSLKDLLSFAIQIAKGMEYL 121

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        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907067260 724 LGSGAFGTVYKGIWVPEGeTVKIPVAIKILNETTGPKANVEFMDEALIMASMDHPHLVRLLGVCLSPTIQLVTQLMPHGC 803
Cdd:cd05060     3 LGHGNFGSVRKGVYLMKS-GKEVEVAVKTLKQEHEKAGKKEFLREASVMAQLDHPCIVRLIGVCKGEPLMLVMELAPLGP 81

                          90       100       110
                  ....*....|....*....|....*....|.
gi 1907067260 804 LLDYVHEHKdNIGSQLLLNWCVQIAKGMMYL 834
Cdd:cd05060    82 LLKYLKKRR-EIPVSDLKELAHQVAMGMAYL 111

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 1907067260 722 KVLGSGAFGTVYKGIWV-PEGETvkIPVAIKIL--NETTGPKANVEFMDEALIMASMDHPHLVRLLGVCLSPTIQLVTQL 798
Cdd:cd05040     1 EKLGDGSFGVVRRGEWTtPSGKV--IQVAVKCLksDVLSQPNAMDDFLKEVNAMHSLDHPNLIRLYGVVLSSPLMMVTEL 78

                          90       100       110
                  ....*....|....*....|....*....|....*.
gi 1907067260 799 MPHGCLLDYVHEHKDNIGSQLLLNWCVQIAKGMMYL 834
Cdd:cd05040    79 APLGSLLDRLRKDQGHFLISTLCDYAVQIANGMAYL 114

Catalytic (repeat 2) domain of the Protein Tyrosine Kinases, Janus kinases; The Jak subfamily is composed of Jak1, Jak2, Jak3, TYK2, and similar proteins. They are PTKs, catalyzing the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. Jaks 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 tyr kinase catalytic domain. 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 protein serine/threonine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907067260 718 LKRVKVLGSGAFGTVYKGIWVPEGETVKIPVAIKILNETTGPKANVEFMDEALIMASMDHPHLVRLLGVCLSP---TIQL 794
Cdd:cd05038     6 LKFIKQLGEGHFGSVELCRYDPLGDNTGEQVAVKSLQPSGEEQHMSDFKREIEILRTLDHEYIVKYKGVCESPgrrSLRL 85

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|...
gi 1907067260 795 VTQLMPHGCLLDYVHEHKDNIGSQLLLNWCVQIAKGMMYlikeLHNMRTTYSD 847
Cdd:cd05038    86 IMEYLPSGSLRDYLQRHRDQIDLKRLLLFASQICKGMEY----LGSQRYIHRD 134

Catalytic domain of the Protein Tyrosine Kinase, Focal Adhesion Kinase; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. FAK is a cytoplasmic (or nonreceptor) PTK that contains an autophosphorylation site and a FERM domain at the N-terminus, a central tyr kinase domain, proline-rich regions, and a C-terminal FAT (focal adhesion targeting) domain. FAK activity is dependent on integrin-mediated cell adhesion, which facilitates N-terminal autophosphorylation. Full activation is achieved by the phosphorylation of its two adjacent A-loop tyrosines. FAK is important in mediating signaling initiated at sites of cell adhesions and at growth factor receptors. Through diverse molecular interactions, FAK functions as a biosensor or integrator to control cell motility. It is a key regulator of cell survival, proliferation, migration and invasion, and thus plays an important role in the development and progression of cancer. Src binds to autophosphorylated FAK forming the FAK-Src dual kinase complex, which is activated in a wide variety of tumor cells and generates signals promoting growth and metastasis. FAK is being developed as a target for cancer therapy. The FAK 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 1907067260 717 ELKRVkvLGSGAFGTVYKGIWV-PEGEtvKIPVAIKILNETTGPKANVEFMDEALIMASMDHPHLVRLLGVCLSPTIQLV 795
Cdd:cd05056     9 TLGRC--IGEGQFGDVYQGVYMsPENE--KIAVAVKTCKNCTSPSVREKFLQEAYIMRQFDHPHIVKLIGVITENPVWIV 84

                          90       100       110
                  ....*....|....*....|....*....|....*....
gi 1907067260 796 TQLMPHGCLLDYVHEHKDNIGSQLLLNWCVQIAKGMMYL 834
Cdd:cd05056    85 MELAPLGELRSYLQVNKYSLDLASLILYAYQLSTALAYL 123

Catalytic domain of Insulin Receptor-like Protein Tyrosine Kinases; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. The InsR subfamily is composed of InsR, Insulin-like Growth Factor-1 Receptor (IGF-1R), and similar proteins. InsR and IGF-1R are receptor PTKs (RTKs) composed of two alphabeta heterodimers. Binding of the ligand (insulin, 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, stimulating downstream kinase activities, which initiate signaling cascades and biological function. InsR and IGF-1R, which share 84% sequence identity in their kinase domains, display physiologically distinct yet overlapping functions in cell growth, differentiation, and metabolism. InsR activation leads primarily to metabolic effects while IGF-1R activation stimulates mitogenic pathways. In cells expressing both receptors, InsR/IGF-1R hybrids are found together with classical receptors. Both receptors can interact with common adaptor molecules such as IRS-1 and IRS-2. The InsR-like subfamily 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 1907067260 717 ELKRVKV-----LGSGAFGTVYKGIW--VPEGEtVKIPVAIKILNETTGPKANVEFMDEALIMASMDHPHLVRLLGVCL- 788
Cdd:cd05032     2 ELPREKItlireLGQGSFGMVYEGLAkgVVKGE-PETRVAIKTVNENASMRERIEFLNEASVMKEFNCHHVVRLLGVVSt 80

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1907067260 789 -SPTIqLVTQLMPHGCLLDYVHEHKDN---------IGSQLLLNWCVQIAKGMMYL 834
Cdd:cd05032    81 gQPTL-VVMELMAKGDLKSYLRSRRPEaennpglgpPTLQKFIQMAAEIADGMAYL 135

Catalytic domain of Ephrin Receptor Protein Tyrosine Kinases; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. EphRs comprise the largest subfamily of receptor PTKs (RTKs). They can be classified into two classes (EphA and EphB), according to their extracellular sequences, which largely correspond to binding preferences for either GPI-anchored ephrin-A ligands or transmembrane ephrin-B ligands. Vertebrates have ten EphA and six EphB receptors, which display promiscuous ligand interactions within each class. 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. This allows ephrin/EphR dimers to form, leading to the activation of the intracellular tyr kinase domain. The resulting downstream signals occur bidirectionally in both EphR-expressing cells (forward signaling) and ephrin-expressing cells (reverse signaling). The main effect of ephrin/EphR interaction is cell-cell repulsion or adhesion. Ephrin/EphR signaling is important in neural development and plasticity, cell morphogenesis and proliferation, cell-fate determination, embryonic development, tissue patterning, and angiogenesis.The EphR 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 1907067260 716 TELKRVKVLGSGAFGTVYKGIWVPEGETVkIPVAIKILNETTGPKANVEFMDEALIMASMDHPHLVRLLGVCL-SPTIQL 794
Cdd:cd05033     4 SYVTIEKVIGGGEFGEVCSGSLKLPGKKE-IDVAIKTLKSGYSDKQRLDFLTEASIMGQFDHPNVIRLEGVVTkSRPVMI 82

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|
gi 1907067260 795 VTQLMPHGCLLDYVHEHKDNIGSQLLLNWCVQIAKGMMYL 834
Cdd:cd05033    83 VTEYMENGSLDKFLRENDGKFTVTQLVGMLRGIASGMKYL 122

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 1907067260 722 KVLGSGAFGTVYKGIWvpEGETvkiPVAIKILNE-TTGPKAnveFMDEALIMASMDHPHLVRLLGVC-LSPTIQLVTQLM 799
Cdd:cd05034     1 KKLGAGQFGEVWMGVW--NGTT---KVAVKTLKPgTMSPEA---FLQEAQIMKKLRHDKLVQLYAVCsDEEPIYIVTELM 72

                          90       100       110
                  ....*....|....*....|....*....|....*....
gi 1907067260 800 PHGCLLDYVhehKDNIGSQL----LLNWCVQIAKGMMYL 834
Cdd:cd05034    73 SKGSLLDYL---RTGEGRALrlpqLIDMAAQIASGMAYL 108

Serine/Threonine protein kinases, catalytic domain; Phosphotransferases. Serine or threonine-specific kinase subfamily.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907067260  719 KRVKVLGSGAFGTVYKGIWVPEGETVkipvAIKILNETTGPKANVEFMDEALIMASMDHPHLVRLLGVCLSPT-IQLVTQ 797
Cdd:smart00220   2 EILEKLGEGSFGKVYLARDKKTGKLV----AIKVIKKKKIKKDRERILREIKILKKLKHPNIVRLYDVFEDEDkLYLVME 77

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|
gi 1907067260  798 LMPHGCLLDYVHEHKdNIGSQLLLNWCVQIAKGMMYlikeLHNMRTTYSD 847
Cdd:smart00220  78 YCEGGDLFDLLKKRG-RLSEDEARFYLRQILSALEY----LHSKGIVHRD 122

Catalytic domain of the Protein Tyrosine Kinases, Tyrosine kinase expressed in hepatocellular carcinoma and Resting lymphocyte kinase; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. Tec and Rlk (also named Txk) are members of the Tec-like subfamily of proteins, which are cytoplasmic (or nonreceptor) PTKs with similarity to Src kinases in that they contain Src homology protein interaction domains (SH3, SH2) N-terminal to the catalytic tyr kinase domain. Unlike Src kinases, most Tec subfamily members except Rlk also contain an N-terminal pleckstrin homology (PH) domain, which binds the products of PI3K and allows membrane recruitment and activation. Instead of PH, Rlk contains an N-terminal cysteine-rich region. In addition to PH, Tec also contains the Tec homology (TH) domain with proline-rich and zinc-binding regions. Tec kinases are expressed mainly by haematopoietic cells. Tec is more widely-expressed than other Tec-like subfamily kinases. It is found in endothelial cells, both B- and T-cells, and a variety of myeloid cells including mast cells, erythroid cells, platelets, macrophages and neutrophils. Rlk is expressed in T-cells and mast cell lines. Tec and Rlk are both key components of T-cell receptor (TCR) signaling. They are important in TCR-stimulated proliferation, IL-2 production and phopholipase C-gamma1 activation. The Tec/Rlk 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 1907067260 713 LKETELKRVKVLGSGAFGTVYKGIWvpegeTVKIPVAIKILNEttGPKANVEFMDEALIMASMDHPHLVRLLGVCLSPT- 791
Cdd:cd05114     1 INPSELTFMKELGSGLFGVVRLGKW-----RAQYKVAIKAIRE--GAMSEEDFIEEAKVMMKLTHPKLVQLYGVCTQQKp 73

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|...
gi 1907067260 792 IQLVTQLMPHGCLLDYVHEHKDNIGSQLLLNWCVQIAKGMMYL 834
Cdd:cd05114    74 IYIVTEFMENGCLLNYLRQRRGKLSRDMLLSMCQDVCEGMEYL 116

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        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907067260 713 LKETELKRVKVLGSGAFGTVYKGIWvpEGETVkipvAIKILNETTgpKANVEFMDEALIMASMDHPHLVRLLGVCL-SPT 791
Cdd:cd05039     3 INKKDLKLGELIGKGEFGDVMLGDY--RGQKV----AVKCLKDDS--TAAQAFLAEASVMTTLRHPNLVQLLGVVLeGNG 74

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....
gi 1907067260 792 IQLVTQLMPHGCLLDYVHEH-KDNIGSQLLLNWCVQIAKGMMYL 834
Cdd:cd05039    75 LYIVTEYMAKGSLVDYLRSRgRAVITRKDQLGFALDVCEGMEYL 118

Protein kinase domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907067260 720 RVKVLGSGAFGTVYKGIwvpEGETVKIpVAIKILN-ETTGPKANVEFMDEALIMASMDHPHLVRLLGVCLSPT-IQLVTQ 797
Cdd:pfam00069   3 VLRKLGSGSFGTVYKAK---HRDTGKI-VAIKKIKkEKIKKKKDKNILREIKILKKLNHPNIVRLYDAFEDKDnLYLVLE 78

                          90       100       110
                  ....*....|....*....|....*....|....
gi 1907067260 798 LMPHGCLLDYVHEHKdNIGSQLLLNWCVQIAKGM 831
Cdd:pfam00069  79 YVEGGSLFDLLSEKG-AFSEREAKFIMKQILEGL 111

Catalytic domain of the Serine/Threonine kinases, Interleukin-1 Receptor Associated Kinases and related STKs; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. IRAKs are involved in Toll-like receptor (TLR) and interleukin-1 (IL-1) signalling pathways, and are thus critical in regulating innate immune responses and inflammation. Some IRAKs may also play roles in T- and B-cell signaling, and adaptive immunity. Vertebrates contain four IRAKs (IRAK-1, -2, -3 (or -M), and -4) that display distinct functions and patterns of expression and subcellular distribution, and can differentially mediate TLR signaling. IRAK-1, -2, and -4 are ubiquitously expressed and are active kinases, while IRAK-M is only induced in monocytes and macrophages and is an inactive kinase. Variations in IRAK genes are linked to diverse diseases including infection, sepsis, cancer, and autoimmune diseases. IRAKs contain an N-terminal Death domain (DD), a proST region (rich in serines, prolines, and threonines), a central kinase domain (a pseudokinase domain in the case of IRAK3), and a C-terminal domain; IRAK-4 lacks the C-terminal domain. This subfamily includes plant receptor-like kinases (RLKs) including Arabidopsis thaliana BAK1 and CLAVATA1 (CLV1). BAK1 functions in BR (brassinosteroid)-regulated plant development and in pathways involved in plant resistance to pathogen infection and herbivore attack. CLV1, directly binds small signaling peptides, CLAVATA3 (CLV3) and CLAVATA3/EMBRYO SURROUNDING REGI0N (CLE), to restrict stem cell proliferation: the CLV3-CLV1-WUS (WUSCHEL) module influences stem cell maintenance in the shoot apical meristem, and the CLE40 (CLAVATA3/EMBRYO SURROUNDING REGION40) -ACR4 (CRINKLY4) -CLV1- WOX5 (WUSCHEL-RELATED HOMEOBOX5) module at the root apical meristem. The IRAK subfamily is part of a larger superfamily that includes the catalytic domains of other protein STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907067260 724 LGSGAFGTVYKGIWvpEGETVkipVAIKILNETTGPKANVEFMDEALIMASMDHPHLVRLLGVCLSPTIQ-LVTQLMPHG 802
Cdd:cd14066     1 IGSGGFGTVYKGVL--ENGTV---VAVKRLNEMNCAASKKEFLTELEMLGRLRHPNLVRLLGYCLESDEKlLVYEYMPNG 75

                          90       100       110
                  ....*....|....*....|....*....|....
gi 1907067260 803 CLLDYVHEHK--DNIGSQLLLNWCVQIAKGMMYL 834
Cdd:cd14066    76 SLEDRLHCHKgsPPLPWPQRLKIAKGIARGLEYL 109