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 545746410   1 MSAAGTYAWMAPEVIRASMFSKGSDVWSYGVLLWELLTGEVPFRGIDGLAVAYGVAMNKLALPIPSTCPEPFAKLMEDCW 80
Cdd:cd14145  171 MSAAGTYAWMAPEVIRSSMFSKGSDVWSYGVLLWELLTGEVPFRGIDGLAVAYGVAMNKLSLPIPSTCPEPFARLMEDCW 250

                         90       100
                 ....*....|....*....|
gi 545746410  81 NPDPHSRPSFTNILDQLTTI 100
Cdd:cd14145  251 NPDPHSRPPFTNILDQLTAI 270

Protein of unknown function (DUF2967); This family of proteins with unknown function appears to be restricted to Drosophila.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 545746410  597 VSPVEAPPLSPCTHNPLVNVRVERFKRDPNQSLTPT----HVTLTTPSQPSSHR---RTPSDGALKPETLLASRSPSSNG 669
Cdd:pfam11179 444 SSQRRHPTGGHSPGSQRQEERRERKEREPSTAPPPTrgreHFTFDPPQSPKSARsseKARSHFSFKEETQQANEAAKDAG 523

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 545746410  670 LSPSPGAGMLKTPSPSRDPGefprLPDPNVVFPPTPRRWNTQQDSTLERPKTLEFLPRPRPSAN-------------RQR 736
Cdd:pfam11179 524 TGSGKGTGSVVGGGGGSGSG----VGGNGVAAAAEADEEDDERSGDLAANRNKKLRARERDTMNanggggggsagstRNH 599

                         170       180       190
                  ....*....|....*....|....*....|....*...
gi 545746410  737 LDPwwFVSPSHARSTSPANSSSTETPSNLDSCFASSSS 774
Cdd:pfam11179 600 ISP--NVSPSHSNRASPKREKKRTMPIASTGAIAKINS 635

Catalytic domain of the Serine/Threonine Kinase, Mixed Lineage Kinase 1; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. MLK1 is a mitogen-activated protein kinase kinase kinase (MAP3K, MKKK, MAPKKK) and is also called MAP3K9. MAP3Ks phosphorylate and activate MAPK kinases (MAPKKs or MKKs or MAP2Ks), which in turn phosphorylate and activate MAPKs during signaling cascades that are important in mediating cellular responses to extracellular signals. Little is known about the specific function of MLK1. It is capable of activating the c-Jun N-terminal kinase pathway. Mice lacking both MLK1 and MLK2 are viable, fertile, and have normal life spans. There could be redundancy in the function of MLKs. Mammals have four MLKs, mostly conserved in vertebrates, which contain an SH3 domain, a catalytic kinase domain, a leucine zipper, a proline-rich region, and a CRIB domain that mediates binding to GTP-bound Cdc42 and Rac. MLKs play roles in immunity and inflammation, as well as in cell death, proliferation, and cell cycle regulation. The MLK1 subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 545746410   1 MSAAGTYAWMAPEVIRASMFSKGSDVWSYGVLLWELLTGEVPFRGIDGLAVAYGVAMNKLALPIPSTCPEPFAKLMEDCW 80
Cdd:cd14145  171 MSAAGTYAWMAPEVIRSSMFSKGSDVWSYGVLLWELLTGEVPFRGIDGLAVAYGVAMNKLSLPIPSTCPEPFARLMEDCW 250

                         90       100
                 ....*....|....*....|
gi 545746410  81 NPDPHSRPSFTNILDQLTTI 100
Cdd:cd14145  251 NPDPHSRPPFTNILDQLTAI 270

Protein kinase domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 545746410    1 MSAAGTYAWMAPEVIRASMFSKGSDVWSYGVLLWELLTGEVPFRGIDGLAVAYGVAMNKLALP-IPSTCPEPFAKLMEDC 79
Cdd:pfam00069 118 TTFVGTPWYMAPEVLGGNPYGPKVDVWSLGCILYELLTGKPPFPGINGNEIYELIIDQPYAFPeLPSNLSEEAKDLLKKL 197

                          90
                  ....*....|....*.
gi 545746410   80 WNPDPHSRPSFTNILD 95
Cdd:pfam00069 198 LKKDPSKRLTATQALQ 213

serine/threonine protein kinase; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 545746410   5 GTYAWMAPEVIRASMFSKGSDVWSYGVLLWELLTGEVPFRGIDGLAVaygvaMNK-LA---LPIPSTCPEPFAKLMEDCW 80
Cdd:PTZ00283 207 GTPYYVAPEIWRRKPYSKKADMFSLGVLLYELLTLKRPFDGENMEEV-----MHKtLAgryDPLPPSISPEMQEIVTALL 281

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 545746410  81 NPDPHSRPSFTNILDQ----------LTTIEESGFFEMPkdsfhcLQDNWKHEIQEMFDQLRA-KEKELRTWEEELTRAA 149
Cdd:PTZ00283 282 SSDPKRRPSSSKLLNMpicklfisglLEIVQTQPGFSGP------LRDTISRQIQQTKQLLQVeRRRIVRQMEESLSTAA 355

Possible nuclease of RNase H fold, RuvC/YqgF family [General function prediction only];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 545746410 121 KHEIQEMFDQLRAKEKELRTWEEELTRAALQQKnqEELLRRREQELAEREIDILERELNiiihqlcQEKPRVKKRKGKFR 200
Cdd:COG2433  426 EAEVEELEAELEEKDERIERLERELSEARSEER--REIRKDREISRLDREIERLERELE-------EERERIEELKRKLE 496

                 ....*
gi 545746410 201 ksRLK 205
Cdd:COG2433  497 --RLK 499

phosphodiesterase; Provisional

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 545746410 123 EIQEMFDQLRAK-EKELRTWEEELTRA--ALQQK-----NQEELLRRREQELAEREIDILERELNI 180
Cdd:PRK12704  61 EAKEEIHKLRNEfEKELRERRNELQKLekRLLQKeenldRKLELLEKREEELEKKEKELEQKQQEL 126

transcriptional regulator ICP4; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 545746410  636 LTTPSQPSSHR-RTPSDGALKPetllASRSPSSNGLSPSPGAGMLKTPSPSRDPGEFPRlpdpnvvfPPTPRRwntqqdS 714
Cdd:PHA03307  308 APSSPRASSSSsSSRESSSSST----SSSSESSRGAAVSPGPSPSRSPSPSRPPPPADP--------SSPRKR------P 369

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 545746410  715 TLERPKTLEFLPRPRPSANRQRLDPwwfVSPSHARSTSPANSSSTETPSNLDSCFASSSSTVEERPGLPALLPF-QAGPL 793
Cdd:PHA03307  370 RPSRAPSSPAASAGRPTRRRARAAV---AGRARRRDATGRFPAGRPRPSPLDAGAASGAFYARYPLLTPSGEPWpGSPPP 446

                  ..
gi 545746410  794 PP 795
Cdd:PHA03307  447 PP 448

Catalytic domain of the Serine/Threonine Kinase, Mixed Lineage Kinase 1; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. MLK1 is a mitogen-activated protein kinase kinase kinase (MAP3K, MKKK, MAPKKK) and is also called MAP3K9. MAP3Ks phosphorylate and activate MAPK kinases (MAPKKs or MKKs or MAP2Ks), which in turn phosphorylate and activate MAPKs during signaling cascades that are important in mediating cellular responses to extracellular signals. Little is known about the specific function of MLK1. It is capable of activating the c-Jun N-terminal kinase pathway. Mice lacking both MLK1 and MLK2 are viable, fertile, and have normal life spans. There could be redundancy in the function of MLKs. Mammals have four MLKs, mostly conserved in vertebrates, which contain an SH3 domain, a catalytic kinase domain, a leucine zipper, a proline-rich region, and a CRIB domain that mediates binding to GTP-bound Cdc42 and Rac. MLKs play roles in immunity and inflammation, as well as in cell death, proliferation, and cell cycle regulation. The MLK1 subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 545746410   1 MSAAGTYAWMAPEVIRASMFSKGSDVWSYGVLLWELLTGEVPFRGIDGLAVAYGVAMNKLALPIPSTCPEPFAKLMEDCW 80
Cdd:cd14145  171 MSAAGTYAWMAPEVIRSSMFSKGSDVWSYGVLLWELLTGEVPFRGIDGLAVAYGVAMNKLSLPIPSTCPEPFARLMEDCW 250

                         90       100
                 ....*....|....*....|
gi 545746410  81 NPDPHSRPSFTNILDQLTTI 100
Cdd:cd14145  251 NPDPHSRPPFTNILDQLTAI 270

Catalytic domain of the Serine/Threonine Kinase, Mixed Lineage Kinase 4; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. MLK4 is a mitogen-activated protein kinase kinase kinase (MAP3K, MKKK, MAPKKK), which phosphorylates and activates MAPK kinases (MAPKKs or MKKs or MAP2Ks), which in turn phosphorylate and activate MAPKs during signaling cascades that are important in mediating cellular responses to extracellular signals. The specific function of MLK4 is yet to be determined. Mutations in the kinase domain of MLK4 have been detected in colorectal cancers. Mammals have four MLKs, mostly conserved in vertebrates, which contain an SH3 domain, a catalytic kinase domain, a leucine zipper, a proline-rich region, and a CRIB domain that mediates binding to GTP-bound Cdc42 and Rac. MLKs play roles in immunity and inflammation, as well as in cell death, proliferation, and cell cycle regulation.The MLK4 subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 545746410   1 MSAAGTYAWMAPEVIRASMFSKGSDVWSYGVLLWELLTGEVPFRGIDGLAVAYGVAMNKLALPIPSTCPEPFAKLMEDCW 80
Cdd:cd14146  169 MSAAGTYAWMAPEVIKSSLFSKGSDIWSYGVLLWELLTGEVPYRGIDGLAVAYGVAVNKLTLPIPSTCPEPFAKLMKECW 248

                         90       100
                 ....*....|....*....|
gi 545746410  81 NPDPHSRPSFTNILDQLTTI 100
Cdd:cd14146  249 EQDPHIRPSFALILEQLTAI 268

Catalytic domain of the Serine/Threonine Kinase, Mixed Lineage Kinase 3; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. MLK3 is a mitogen-activated protein kinase kinase kinases (MAP3K, MKKK, MAPKKK), which phosphorylates and activates MAPK kinases (MAPKKs or MKKs or MAP2Ks), which in turn phosphorylate and activate MAPKs during signaling cascades that are important in mediating cellular responses to extracellular signals. MLK3 activates multiple MAPK pathways and plays a role in apoptosis, proliferation, migration, and differentiation, depending on the cellular context. It is highly expressed in breast cancer cells and its signaling through c-Jun N-terminal kinase has been implicated in the migration, invasion, and malignancy of cancer cells. MLK3 also functions as a negative regulator of Inhibitor of Nuclear Factor-KappaB Kinase (IKK) and consequently, it also impacts inflammation and immunity. Mammals have four MLKs, mostly conserved in vertebrates, which contain an SH3 domain, a catalytic kinase domain, a leucine zipper, a proline-rich region, and a CRIB domain that mediates binding to GTP-bound Cdc42 and Rac. MLKs play roles in immunity and inflammation, as well as in cell death, proliferation, and cell cycle regulation.The MLK3 subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 545746410   1 MSAAGTYAWMAPEVIRASMFSKGSDVWSYGVLLWELLTGEVPFRGIDGLAVAYGVAMNKLALPIPSTCPEPFAKLMEDCW 80
Cdd:cd14147  168 MSAAGTYAWMAPEVIKASTFSKGSDVWSFGVLLWELLTGEVPYRGIDCLAVAYGVAVNKLTLPIPSTCPEPFAQLMADCW 247

                         90       100
                 ....*....|....*....|
gi 545746410  81 NPDPHSRPSFTNILDQLTTI 100
Cdd:cd14147  248 AQDPHRRPDFASILQQLEAL 267

Catalytic domain of the Serine/Threonine Kinases, Mitogen-Activated Protein Kinase Kinase Kinases 12 and 13; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. MAP3K12 is also called MAPK upstream kinase (MUK), dual leucine zipper-bearing kinase (DLK) or leucine-zipper protein kinase (ZPK). It is involved in the c-Jun N-terminal kinase (JNK) pathway that directly regulates axonal regulation through the phosphorylation of microtubule-associated protein 1B (MAP1B). It also regulates the differentiation of many cell types including adipocytes and may play a role in adipogenesis. MAP3K13, also called leucine zipper-bearing kinase (LZK), directly phosphorylates and activates MKK7, which in turn activates the JNK pathway. It also activates NF-kB through IKK activation and this activity is enhanced by antioxidant protein-1 (AOP-1). MAP3Ks (MKKKs or MAPKKKs) phosphorylate and activate MAP2Ks (MAPKKs or MKKs), which in turn phosphorylate and activate MAPKs during signaling cascades that are important in mediating cellular responses to extracellular signals. The MAP3K12/13 subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 545746410   1 MSAAGTYAWMAPEVIRASMFSKGSDVWSYGVLLWELLTGEVPFRGIDGLAVAYGVAMNKLALPIPSTCPEPFAKLMEDCW 80
Cdd:cd14059  138 MSFAGTVAWMAPEVIRNEPCSEKVDIWSFGVVLWELLTGEIPYKDVDSSAIIWGVGSNSLQLPVPSTCPDGFKLLMKQCW 217

                         90
                 ....*....|....*..
gi 545746410  81 NPDPHSRPSFTNILDQL 97
Cdd:cd14059  218 NSKPRNRPSFRQILMHL 234

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        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 545746410     7 YAWMAPEVIRASMFSKGSDVWSYGVLLWELLT-GEVPFRGIDgLAVAYGVAMNKLALPIPSTCPEPFAKLMEDCWNPDPH 85
Cdd:smart00221 168 IRWMAPESLKEGKFTSKSDVWSFGVLLWEIFTlGEEPYPGMS-NAEVLEYLKKGYRLPKPPNCPPELYKLMLQCWAEDPE 246

                           90
                   ....*....|..
gi 545746410    86 SRPSFTNILDQL 97
Cdd:smart00221 247 DRPTFSELVEIL 258

Protein kinase domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 545746410    1 MSAAGTYAWMAPEVIRASMFSKGSDVWSYGVLLWELLTGEVPFRGIDGLAVAYGVAMNKLALP-IPSTCPEPFAKLMEDC 79
Cdd:pfam00069 118 TTFVGTPWYMAPEVLGGNPYGPKVDVWSLGCILYELLTGKPPFPGINGNEIYELIIDQPYAFPeLPSNLSEEAKDLLKKL 197

                          90
                  ....*....|....*.
gi 545746410   80 WNPDPHSRPSFTNILD 95
Cdd:pfam00069 198 LKKDPSKRLTATQALQ 213

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 545746410   9 WMAPEVIRASMFSKGSDVWSYGVLLWELLT-GEVPFRGIDGLAVAYGVaMNKLALPIPSTCPEPFAKLMEDCWNPDPHSR 87
Cdd:cd00192  173 WMAPESLKDGIFTSKSDVWSFGVLLWEIFTlGATPYPGLSNEEVLEYL-RKGYRLPKPENCPDELYELMLSCWQLDPEDR 251

                         90
                 ....*....|.
gi 545746410  88 PSFTNILDQLT 98
Cdd:cd00192  252 PTFSELVERLE 262

Catalytic domain of the Serine/Threonine Kinase, Transforming Growth Factor beta Activated Kinase-1; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. TAK1 is also known as mitogen-activated protein kinase kinase kinase 7 (MAPKKK7 or MAP3K7), TAK, or MEKK7. As a MAPKKK, it is an important mediator of cellular responses to extracellular signals. It regulates both the c-Jun N-terminal kinase and p38 MAPK cascades by activating the MAPK kinases, MKK4 and MKK3/6. In addition, TAK1 plays diverse roles in immunity and development, in different biological contexts, through many signaling pathways including TGFbeta/BMP, Wnt/Fz, and NF-kB. It is also implicated in the activation of the tumor suppressor kinase, LKB1. The TAK1 subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 545746410   5 GTYAWMAPEVIRASMFSKGSDVWSYGVLLWELLTGEVPFRGIDGLAVAYGVAMNKLA-LPIPSTCPEPFAKLMEDCWNPD 83
Cdd:cd14058  152 GSAAWMAPEVFEGSKYSEKCDVFSWGIILWEVITRRKPFDHIGGPAFRIMWAVHNGErPPLIKNCPKPIESLMTRCWSKD 231

                         90       100
                 ....*....|....*....|.
gi 545746410  84 PHSRPSFTNILDQLTTIEESG 104
Cdd:cd14058  232 PEKRPSMKEIVKIMSHLMQFF 252

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 545746410   7 YAWMAPEVIRASMFSKGSDVWSYGVLLWELLT-GEVPFRGIDGLAVAYGVAMNKLALPIPSTCPEPFAKLMEDCWNPDPH 85
Cdd:cd05040  165 FAWCAPESLKTRKFSHASDVWMFGVTLWEMFTyGEEPWLGLNGSQILEKIDKEGERLERPDDCPQDIYNVMLQCWAHKPA 244

                         90
                 ....*....|...
gi 545746410  86 SRPSFTNILDQLT 98
Cdd:cd05040  245 DRPTFVALRDFLP 257

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 545746410   9 WMAPEVIRASMFSKGSDVWSYGVLLWELLT-GEVPFRGIdGLA-----VAYGVAMNKlalpiPSTCPEPFAKLMEDCWNP 82
Cdd:cd05039  165 WTAPEALREKKFSTKSDVWSFGILLWEIYSfGRVPYPRI-PLKdvvphVEKGYRMEA-----PEGCPPEVYKVMKNCWEL 238

                         90
                 ....*....|....*...
gi 545746410  83 DPHSRPSFTNILDQLTTI 100
Cdd:cd05039  239 DPAKRPTFKQLREKLEHI 256

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 545746410   9 WMAPEVIRASMFSKGSDVWSYGVLLWELLT-GEVPFRGIDGLAVAYGVAMNkLALPIPSTCPEPFAKLMEDCWNPDPHSR 87
Cdd:cd05068  172 WTAPEAANYNRFSIKSDVWSFGILLTEIVTyGRIPYPGMTNAEVLQQVERG-YRMPCPPNCPPQLYDIMLECWKADPMER 250

                         90       100
                 ....*....|....*....|.
gi 545746410  88 PSFTNILDQLttiEEsgFFEM 108
Cdd:cd05068  251 PTFETLQWKL---ED--FFVN 266

Catalytic domain of the Protein Tyrosine Kinases, Met and Ron; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. Met and Ron are receptor PTKs (RTKs) composed of an alpha-beta heterodimer. The extracellular alpha chain is disulfide linked to the beta chain, which contains an extracellular ligand-binding region with a sema domain, a PSI domain and four IPT repeats, a transmembrane segment, and an intracellular catalytic domain. Binding to their ligands leads to receptor dimerization, autophosphorylation, activation, and intracellular signaling. Met binds to the ligand, hepatocyte growth factor/scatter factor (HGF/SF), and is also called the HGF receptor. HGF/Met signaling plays a role in growth, transformation, cell motility, invasion, metastasis, angiogenesis, wound healing, and tissue regeneration. Aberrant expression of Met through mutations or gene amplification is associated with many human cancers including hereditary papillary renal and gastric carcinomas. The ligand for Ron is macrophage stimulating protein (MSP). Ron signaling is important in regulating cell motility, adhesion, proliferation, and apoptosis. Aberrant Ron expression is implicated in tumorigenesis and metastasis. The Met/Ron 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 545746410   9 WMAPEVIRASMFSKGSDVWSYGVLLWELLT-GEVPFRGIDGLAVAYGVAMNKlALPIPSTCPEPFAKLMEDCWNPDPHSR 87
Cdd:cd05058  168 WMALESLQTQKFTTKSDVWSFGVLLWELMTrGAPPYPDVDSFDITVYLLQGR-RLLQPEYCPDPLYEVMLSCWHPKPEMR 246

                         90
                 ....*....|...
gi 545746410  88 PSFTNILDQLTTI 100
Cdd:cd05058  247 PTFSELVSRISQI 259

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 545746410   9 WMAPEVIRASMFSKGSDVWSYGVLLWELLT-GEVPFRGIDGLAVAYGVaMNKLALPIPSTCPEPFAKLMEDCWNPDPHSR 87
Cdd:cd05033  174 WTAPEAIAYRKFTSASDVWSFGIVMWEVMSyGERPYWDMSNQDVIKAV-EDGYRLPPPMDCPSALYQLMLDCWQKDRNER 252

                         90
                 ....*....|
gi 545746410  88 PSFTNILDQL 97
Cdd:cd05033  253 PTFSQIVSTL 262

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 545746410   9 WMAPEVIRASMFSKGSDVWSYGVLLWELLT-GEVPFRGIDGLAVAyGVAMNKLALPIPSTCPEPFAKLMEDCWNPDPHSR 87
Cdd:cd05056  174 WMAPESINFRRFTSASDVWMFGVCMWEILMlGVKPFQGVKNNDVI-GRIENGERLPMPPNCPPTLYSLMTKCWAYDPSKR 252

                         90
                 ....*....|....*
gi 545746410  88 PSFTNILDQLTTIEE 102
Cdd:cd05056  253 PRFTELKAQLSDILQ 267

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.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 545746410   9 WMAPEVIRASMFSKGSDVWSYGVLLWELLT-GEVPFRGIDGLAVAYGVAmNKLALPIPSTCPEPFAKLMEDCWNPDPHSR 87
Cdd:cd05044  178 WMAPESLVDGVFTTQSDVWAFGVLMWEILTlGQQPYPARNNLEVLHFVR-AGGRLDQPDNCPDDLYELMLRCWSTDPEER 256

                         90
                 ....*....|
gi 545746410  88 PSFTNILDQL 97
Cdd:cd05044  257 PSFARILEQL 266

Catalytic domain of the Protein Tyrosine Kinase, Abelson kinase; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. Abl (or c-Abl) is a ubiquitously-expressed cytoplasmic (or nonreceptor) PTK that contains SH3, SH2, and tyr kinase domains in its N-terminal region, as well as nuclear localization motifs, a putative DNA-binding domain, and F- and G-actin binding domains in its C-terminal tail. It also contains a short autoinhibitory cap region in its N-terminus. Abl function depends on its subcellular localization. In the cytoplasm, Abl plays a role in cell proliferation and survival. In response to DNA damage or oxidative stress, Abl is transported to the nucleus where it induces apoptosis. In chronic myelogenous leukemia (CML) patients, an aberrant translocation results in the replacement of the first exon of Abl with the BCR (breakpoint cluster region) gene. The resulting BCR-Abl fusion protein is constitutively active and associates into tetramers, resulting in a hyperactive kinase sending a continuous signal. This leads to uncontrolled proliferation, morphological transformation and anti-apoptotic effects. BCR-Abl is the target of selective inhibitors, such as imatinib (Gleevec), used in the treatment of CML. Abl2, also known as ARG (Abelson-related gene), is thought to play a cooperative role with Abl in the proper development of the nervous system. The Tel-ARG fusion protein, resulting from reciprocal translocation between chromosomes 1 and 12, is associated with acute myeloid leukemia (AML). The TEL gene is a frequent fusion partner of other tyr kinase oncogenes, including Tel/Abl, Tel/PDGFRbeta, and Tel/Jak2, found in patients with leukemia and myeloproliferative disorders. The Abl 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 545746410   9 WMAPEVIRASMFSKGSDVWSYGVLLWELLT-GEVPFRGIDgLAVAYGVAMNKLALPIPSTCPEPFAKLMEDCWNPDPHSR 87
Cdd:cd05052  171 WTAPESLAYNKFSIKSDVWAFGVLLWEIATyGMSPYPGID-LSQVYELLEKGYRMERPEGCPPKVYELMRACWQWNPSDR 249

                         90
                 ....*....|...
gi 545746410  88 PSFTNILDQLTTI 100
Cdd:cd05052  250 PSFAEIHQALETM 262

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 545746410   9 WMAPEVIRASMFSKGSDVWSYGVLLWELLT-GEVPFRGIDGLAVAYGVAMNKLA-------------LPIPSTCPEPFAK 74
Cdd:cd05038  178 WYAPECLRESRFSSASDVWSFGVTLYELFTyGDPSQSPPALFLRMIGIAQGQMIvtrllellksgerLPRPPSCPDEVYD 257

                         90       100
                 ....*....|....*....|....*.
gi 545746410  75 LMEDCWNPDPHSRPSFTNILDQLTTI 100
Cdd:cd05038  258 LMKECWEYEPQDRPSFSDLILIIDRL 283

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 545746410   9 WMAPEVIRASMFSKGSDVWSYGVLLWELLT-GEVPFRGIDGLAVAYGVAmNKLALPIPSTCPEPFAKLMEDCWNPDPHSR 87
Cdd:cd05057  177 WMALESIQYRIYTHKSDVWSYGVTVWELMTfGAKPYEGIPAVEIPDLLE-KGERLPQPPICTIDVYMVLVKCWMIDAESR 255

                         90
                 ....*....|..
gi 545746410  88 PSFTNILDQLTT 99
Cdd:cd05057  256 PTFKELANEFSK 267

Catalytic Domain of the Protein Tyrosine Kinases, Receptor tyrosine kinase-like Orphan Receptors; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. The Ror subfamily consists of Ror1, Ror2, and similar proteins. Ror proteins are orphan receptor PTKs (RTKs) containing an extracellular region with immunoglobulin-like, cysteine-rich, and kringle domains, a transmembrane segment, and an intracellular catalytic domain. Ror RTKs are unrelated to the nuclear receptor subfamily called retinoid-related orphan receptors (RORs). RTKs are usually activated through ligand binding, which causes dimerization and autophosphorylation of the intracellular tyr kinase catalytic domain. Ror kinases are expressed in many tissues during development. They play important roles in bone and heart formation. Mutations in human Ror2 result in two different bone development genetic disorders, recessive Robinow syndrome and brachydactyly type B. Drosophila Ror is expressed only in the developing nervous system during neurite outgrowth and neuronal differentiation, suggesting a role for Drosophila Ror in neural development. More recently, mouse Ror1 and Ror2 have also been found to play an important role in regulating neurite growth in central neurons. Ror1 and Ror2 are believed to have some overlapping and redundant functions. The Ror 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 545746410   9 WMAPEVIRASMFSKGSDVWSYGVLLWELLT-GEVPFRGIDGLAVAYGVAMNKLaLPIPSTCPEPFAKLMEDCWNPDPHSR 87
Cdd:cd05048  192 WMPPEAILYGKFTTESDVWSFGVVLWEIFSyGLQPYYGYSNQEVIEMIRSRQL-LPCPEDCPARVYSLMVECWHEIPSRR 270

                         90
                 ....*....|..
gi 545746410  88 PSFTNILDQLTT 99
Cdd:cd05048  271 PRFKEIHTRLRT 282

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        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 545746410   9 WMAPEVIRASMFSKGSDVWSYGVLLWELLT-GEVPFRGIDGLAV-AYGVAMNKLALPIpsTCPEPFAKLMEDCWNPDPHS 86
Cdd:cd05074  191 WLALESLADNVYTTHSDVWAFGVTMWEIMTrGQTPYAGVENSEIyNYLIKGNRLKQPP--DCLEDVYELMCQCWSPEPKC 268

                         90
                 ....*....|....
gi 545746410  87 RPSFTNILDQLTTI 100
Cdd:cd05074  269 RPSFQHLRDQLELI 282

Catalytic domain of the Protein Tyrosine Kinases, Anaplastic Lymphoma Kinase and Leukocyte Tyrosine Kinase; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyr residues in protein substrates. ALK and LTK are orphan receptor PTKs (RTKs) whose ligands are not yet well-defined. ALK appears to play an important role in mammalian neural development as well as visceral muscle differentiation in Drosophila. ALK is aberrantly expressed as fusion proteins, due to chromosomal translocations, in about 60% of anaplastic large cell lymphomas (ALCLs). ALK fusion proteins are also found in rare cases of diffuse large B cell lymphomas (DLBCLs). LTK is mainly expressed in B lymphocytes and neuronal tissues. It is important in cell proliferation and survival. Transgenic mice expressing TLK display retarded growth and high mortality rate. In addition, a polymorphism in mouse and human LTK is implicated in the pathogenesis of systemic lupus erythematosus. RTKs contain an extracellular ligand-binding domain, a transmembrane region, and an intracellular tyr kinase domain. They are usually activated through ligand binding, which causes dimerization and autophosphorylation of the intracellular tyr kinase catalytic domain. The ALK/LTK 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 545746410   9 WMAPEVIRASMFSKGSDVWSYGVLLWELLT-GEVPFRGIDGLAVAYGVAMNKLALPiPSTCPEPFAKLMEDCWNPDPHSR 87
Cdd:cd05036  187 WMPPEAFLDGIFTSKTDVWSFGVLLWEIFSlGYMPYPGKSNQEVMEFVTSGGRMDP-PKNCPGPVYRIMTQCWQHIPEDR 265

                         90
                 ....*....|.
gi 545746410  88 PSFTNILDQLT 98
Cdd:cd05036  266 PNFSTILERLN 276

Catalytic domain of the Serine/Threonine Kinases, Raf (Rapidly Accelerated Fibrosarcoma) kinases; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. Raf kinases act as mitogen-activated protein kinase kinase kinases (MAP3Ks, MKKKs, MAPKKKs), which phosphorylate and activate MAPK kinases (MAPKKs or MKKs or MAP2Ks), which in turn phosphorylate and activate MAPKs during signaling cascades that are important in mediating cellular responses to extracellular signals. They function in the linear Ras-Raf-MEK-ERK pathway that regulates many cellular processes including cycle regulation, proliferation, differentiation, survival, and apoptosis. Aberrant expression or activation of components in this pathway are associated with tumor initiation, progression, and metastasis. Raf proteins contain a Ras binding domain, a zinc finger cysteine-rich domain, and a catalytic kinase domain. Vertebrates have three Raf isoforms (A-, B-, and C-Raf) with different expression profiles, modes of regulation, and abilities to function in the ERK cascade, depending on cellular context and stimuli. They have essential and non-overlapping roles during embryo- and organogenesis. Knockout of each isoform results in a lethal phenotype or abnormality in most mouse strains. The Raf subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 545746410   5 GTYAWMAPEVIR---ASMFSKGSDVWSYGVLLWELLTGEVPFRGIDG-----LAVAYGVAMNKLALpIPSTCPEPFAKLM 76
Cdd:cd14062  153 GSILWMAPEVIRmqdENPYSFQSDVYAFGIVLYELLTGQLPYSHINNrdqilFMVGRGYLRPDLSK-VRSDTPKALRRLM 231

                         90       100
                 ....*....|....*....|.
gi 545746410  77 EDCWNPDPHSRPSFTNILDQL 97
Cdd:cd14062  232 EDCIKFQRDERPLFPQILASL 252

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        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 545746410   9 WMAPEVIRASMFSKGSDVWSYGVLLWELLT-GEVPFRGIDGLAVAYGVAmNKLALPIPSTCPEPFAKLMEDCWNPDPHSR 87
Cdd:cd05066  175 WTAPEAIAYRKFTSASDVWSYGIVMWEVMSyGERPYWEMSNQDVIKAIE-EGYRLPAPMDCPAALHQLMLDCWQKDRNER 253

                         90
                 ....*....|...
gi 545746410  88 PSFT---NILDQL 97
Cdd:cd05066  254 PKFEqivSILDKL 266

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        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 545746410   9 WMAPEVIRASMFSKGSDVWSYGVLLWELLT-GEVPFRGIDGLAVAYGVAMNkLALPIPSTCPEPFAKLMEDCWNPDPHSR 87
Cdd:cd05072  171 WTAPEAINFGSFTIKSDVWSFGILLYEIVTyGKIPYPGMSNSDVMSALQRG-YRMPRMENCPDELYDIMKTCWKEKAEER 249

                         90       100
                 ....*....|....*....|.
gi 545746410  88 PSF---TNILDQLTTIEESGF 105
Cdd:cd05072  250 PTFdylQSVLDDFYTATEGQY 270