Serine rich Four helix bundle domain of CAS (Crk-Associated Substrate) scaffolding proteins; a protein interaction module; CAS proteins function as molecular scaffolds to regulate protein complexes that are involved in many cellular processes including migration, chemotaxis, apoptosis, differentiation, and progenitor cell function. They mediate the signaling of integrins at focal adhesions where they localize, and thus, regulate cell invasion and survival. Over-expression of these proteins is implicated in poor prognosis, increased metastasis, and resistance to chemotherapeutics in many cancers such as breast, lung, melanoma, and glioblastoma. CAS proteins have also been linked to the pathogenesis of inflammatory disorders, Alzheimer's, Parkinson's, and developmental defects. They share a common domain structure containing protein interaction modules that enable their scaffolding function, including an N-terminal SH3 domain, an unstructured substrate domain that contains many YxxP motifs, a serine-rich four-helix bundle, and a FAT-like C-terminal domain. Vertebrates contain four CAS proteins: BCAR1 (or p130Cas), NEDD9 (or HEF1), EFS (or SIN), and CASS4 (or HEPL). CAS proteins associate with the 14-3-3 family; this interaction is regulated by integrin-mediated cell adhesion. The serine rich four helix bundle domain of BCAR1 has been shown to bind 14-3-3 in a phosphorylation-dependent manner. This domain is structurally similar to other helical bundles found in cell adhesion components such as alpha-catenin, vinculin, and FAK, and may bind other proteins in addition to the 14-3-3 family.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 282398118 472 LELEVAVEALARLQQGVSATVAHLLDLAGsagatGSWRSPSEPqEPLVQDLQAAVAAVQSAVHELLEFARSAVGNAAHTS 551
Cdd:cd11552    1 LDLEAAMETLARLQQGVSSSVSHLMSFIG-----GNWRSPEHM-EANVQDIHAAVEGVHGAVRELLEFARGAVSNAAQAS 74

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 282398118 552 DRALHAKLSRQLQKMEDVHQTLVAHGQALDAGRGGSGA------TLEDLDRLVACSRAVPEDAKQLASFLHGNASLLFRR 625
Cdd:cd11552   75 DRTLHAKLSRQLQKMEEVYQTLVRHSQALDACRWSPAAlaapgpTLDDLDRLVMYSRGVPDDAKQLASFLHGNASLLFRR 154

                 ...
gi 282398118 626 TKA 628
Cdd:cd11552  155 TKA 157

large tegument protein UL36; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 282398118   91 APAPPASQYTPMLPNTYQPQPDSVYLVPTPSKAQQGLYQVPGPSPQFQSPPAKQTSTFSKQTPHHPFPSPATDLYQVPPG 170
Cdd:PHA03247 2762 TTAGPPAPAPPAAPAAGPPRRLTRPAVASLSESRESLPSPWDPADPPAAVLAPAAALPPAASPAGPLPPPTSAQPTAPPP 2841

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 282398118  171 PGGPAQDIYQVPPSAGMGHDIYQVPPSmdtrswegTKPPAKVVVPTRVGqgyVYEAAQPEQDEYDIPRHLLAPGPqdiyd 250
Cdd:PHA03247 2842 PPGPPPPSLPLGGSVAPGGDVRRRPPS--------RSPAAKPAAPARPP---VRRLARPAVSRSTESFALPPDQP----- 2905

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 282398118  251 vPPVRGLLPSQYGQEVYDTPPMAVKGPNGRDPLLEVYDVPPSVEKGLPPSNHHAVSKCQGNARARLRLWGVWVYDVPPSV 330
Cdd:PHA03247 2906 -ERPPQPQAPPPPQPQPQPPPPPQPQPPPPPPPRPQPPLAPTTDPAGAGEPSGAVPQPWLGALVPGRVAVPRFRVPQPAP 2984

                         250       260       270       280       290       300       310       320
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 282398118  331 SKDVPDGPLLREETYDVPP----AFAKAKPFDPARTPLVLAAPPPDSPPAEDVYDVPPPAPDLYDVPPGLRRPGPGTLYD 406
Cdd:PHA03247 2985 SREAPASSTPPLTGHSLSRvsswASSLALHEETDPPPVSLKQTLWPPDDTEDSDADSLFDSDSERSDLEALDPLPPEPHD 3064

                         330       340       350       360       370       380       390       400
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 282398118  407 VPRERVLPPEVADGGVVDSGVYAVPPPAerEAPAEGKRLSASSTGSTRssqsasslevagpgrepleLEVAVEALARLQQ 486
Cdd:PHA03247 3065 PFAHEPDPATPEAGARESPSSQFGPPPL--SANAALSRRYVRSTGRSA-------------------LAVLIEACRRIRR 3123

                         410
                  ....*....|....*
gi 282398118  487 GVSATVAHLLDLAGS 501
Cdd:PHA03247 3124 QLRRTRHALLDRSGA 3138

C-terminal FAT-like Four helix bundle domain, also called DUF3513, of CAS (Crk-Associated Substrate) scaffolding protein, Breast Cancer Anti-estrogen Resistance 1; a protein interaction module; BCAR1, also called p130cas or CASS1, is the founding member of the CAS family of scaffolding proteins and was originally identified through its ability to associate with Crk. The name BCAR1 was designated because the human gene was identified in a screen for genes that promote resistance to tamoxifen. It is widely expressed and its deletion is lethal in mice. It plays a role in regulating cell motility, survival, proliferation, transformation, cancer progression, and bacterial pathogenesis. CAS proteins function as molecular scaffolds to regulate protein complexes that are involved in many cellular processes. They share a common domain structure containing protein interaction modules that enable their scaffolding function, including an N-terminal SH3 domain, an unstructured substrate domain that contains many YxxP motifs, a serine-rich four-helix bundle, and a FAT-like C-terminal domain, which binds to the C-terminal domain of NSPs (novel SH2-containing proteins) to form multidomain signaling modules that mediate cell migration and invasion.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 282398118 753 GLGPSDRQLLLFYLEQCEANLTTLTNAVDAFFTAVATNQPPKIFVAHSKFVILSAHKLVFIGDTLSRQAKAADVRSQVTH 832
Cdd:cd11569    1 ALGPSDRQLLLFYQEQCEANVTTLTNAIDAFFTSISSNQPPKIFVAHSKFVILSAHKLVFIGDTLSRQAKAADVRSKVTH 80

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|...
gi 282398118 833 YSNLLCDLLRGIVATTKAAALQYPSPSAAQDMVERVKELGHSTQQFRRVLGQL 885
Cdd:cd11569   81 YSNLLCEKLKEIVLSTKTAALQYPSPAAAKDMVERVKELGGSTQQFRMVLGQL 133

Serine rich protein interaction domain; This is a serine rich domain that is found in the docking protein p130(cas) (Crk-associated substrate). This domain folds into a four helix bundle which is associated with protein-protein interactions.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 282398118  472 LELEVAVEALARLQQGVSATVAHLLDLAGSagatgSWRSPsEPQEPLVQDLQAAVAAVQSAVHELLEFARSAVGNAAHTS 551
Cdd:pfam08824   1 LDLDSALETLSRLQQEVESSVSKLMSFVSS-----NWRSR-ENLEAHLNEIRRAVDRVRQSLREFLEFARGAVGNAAQLT 74

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 282398118  552 DRALHAKLSRQLQKMEDVHQTLVAHGQALDAG--------RGGSGATLEDLDRLVACSRAVPEDAKQLASFLHGNASLLF 623
Cdd:pfam08824  75 DSNLQTKLRKQLQRLEDSYQILLQTSQALDSCgwsldvlaTDKPQNSPDDLDRFVMVARTVPDDVKQLASIIQGNGSLLF 154

                  ...
gi 282398118  624 RRT 626
Cdd:pfam08824 155 KRA 157

Src homology 3 domains; Src homology 3 (SH3) domains bind to target proteins through sequences containing proline and hydrophobic amino acids. Pro-containing polypeptides may bind to SH3 domains in 2 different binding orientations.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*
gi 282398118     8 AKALYDNVAESPDELSFRKGDIMTVLEQDTqglDGWWLCSLH-GRQGIVPGNRLK 61
Cdd:smart00326   5 VRALYDYTAQDPDELSFKKGDIITVLEKSD---DGWWKGRLGrGKEGLFPSNYVE 56

large tegument protein UL36; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 282398118   91 APAPPASQYTPMLPNTYQPQPDSVYLVPTPSKAQQGLYQVPGPSPQFQSPPAKQTSTFSKQTPHHPFPSPATDLYQVPPG 170
Cdd:PHA03247 2762 TTAGPPAPAPPAAPAAGPPRRLTRPAVASLSESRESLPSPWDPADPPAAVLAPAAALPPAASPAGPLPPPTSAQPTAPPP 2841

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 282398118  171 PGGPAQDIYQVPPSAGMGHDIYQVPPSmdtrswegTKPPAKVVVPTRVGqgyVYEAAQPEQDEYDIPRHLLAPGPqdiyd 250
Cdd:PHA03247 2842 PPGPPPPSLPLGGSVAPGGDVRRRPPS--------RSPAAKPAAPARPP---VRRLARPAVSRSTESFALPPDQP----- 2905

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 282398118  251 vPPVRGLLPSQYGQEVYDTPPMAVKGPNGRDPLLEVYDVPPSVEKGLPPSNHHAVSKCQGNARARLRLWGVWVYDVPPSV 330
Cdd:PHA03247 2906 -ERPPQPQAPPPPQPQPQPPPPPQPQPPPPPPPRPQPPLAPTTDPAGAGEPSGAVPQPWLGALVPGRVAVPRFRVPQPAP 2984

                         250       260       270       280       290       300       310       320
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 282398118  331 SKDVPDGPLLREETYDVPP----AFAKAKPFDPARTPLVLAAPPPDSPPAEDVYDVPPPAPDLYDVPPGLRRPGPGTLYD 406
Cdd:PHA03247 2985 SREAPASSTPPLTGHSLSRvsswASSLALHEETDPPPVSLKQTLWPPDDTEDSDADSLFDSDSERSDLEALDPLPPEPHD 3064

                         330       340       350       360       370       380       390       400
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 282398118  407 VPRERVLPPEVADGGVVDSGVYAVPPPAerEAPAEGKRLSASSTGSTRssqsasslevagpgrepleLEVAVEALARLQQ 486
Cdd:PHA03247 3065 PFAHEPDPATPEAGARESPSSQFGPPPL--SANAALSRRYVRSTGRSA-------------------LAVLIEACRRIRR 3123

                         410
                  ....*....|....*
gi 282398118  487 GVSATVAHLLDLAGS 501
Cdd:PHA03247 3124 QLRRTRHALLDRSGA 3138

C-terminal FAT-like Four helix bundle domain, also called DUF3513, of CAS (Crk-Associated Substrate) scaffolding protein, Breast Cancer Anti-estrogen Resistance 1; a protein interaction module; BCAR1, also called p130cas or CASS1, is the founding member of the CAS family of scaffolding proteins and was originally identified through its ability to associate with Crk. The name BCAR1 was designated because the human gene was identified in a screen for genes that promote resistance to tamoxifen. It is widely expressed and its deletion is lethal in mice. It plays a role in regulating cell motility, survival, proliferation, transformation, cancer progression, and bacterial pathogenesis. CAS proteins function as molecular scaffolds to regulate protein complexes that are involved in many cellular processes. They share a common domain structure containing protein interaction modules that enable their scaffolding function, including an N-terminal SH3 domain, an unstructured substrate domain that contains many YxxP motifs, a serine-rich four-helix bundle, and a FAT-like C-terminal domain, which binds to the C-terminal domain of NSPs (novel SH2-containing proteins) to form multidomain signaling modules that mediate cell migration and invasion.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 282398118 753 GLGPSDRQLLLFYLEQCEANLTTLTNAVDAFFTAVATNQPPKIFVAHSKFVILSAHKLVFIGDTLSRQAKAADVRSQVTH 832
Cdd:cd11569    1 ALGPSDRQLLLFYQEQCEANVTTLTNAIDAFFTSISSNQPPKIFVAHSKFVILSAHKLVFIGDTLSRQAKAADVRSKVTH 80

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|...
gi 282398118 833 YSNLLCDLLRGIVATTKAAALQYPSPSAAQDMVERVKELGHSTQQFRRVLGQL 885
Cdd:cd11569   81 YSNLLCEKLKEIVLSTKTAALQYPSPAAAKDMVERVKELGGSTQQFRMVLGQL 133

Serine rich Four helix bundle domain of CAS (Crk-Associated Substrate) scaffolding protein, Breast Cancer Anti-estrogen Resistance 1; a protein interaction module; BCAR1, also called p130cas or CASS1, is the founding member of the CAS family of scaffolding proteins and was originally identified through its ability to associate with Crk. The name BCAR1 was designated because the human gene was identified in a screen for genes that promote resistance to tamoxifen. It is widely expressed and its deletion is lethal in mice. It plays a role in regulating cell motility, survival, proliferation, transformation, cancer progression, and bacterial pathogenesis. CAS proteins function as molecular scaffolds to regulate protein complexes that are involved in many cellular processes. They share a common domain structure containing protein interaction modules that enable their scaffolding function, including an N-terminal SH3 domain, an unstructured substrate domain that contains many YxxP motifs, a serine-rich four-helix bundle, and a FAT-like C-terminal domain. CAS proteins associate with the 14-3-3 family; this interaction is regulated by integrin-mediated cell adhesion. The serine rich four helix bundle domain of BCAR1 has been shown to bind 14-3-3 in a phosphorylation-dependent manner. This domain is structurally similar to other helical bundles found in cell adhesion components such as alpha-catenin, vinculin, and FAK, and may bind other proteins in addition to the 14-3-3 family.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 282398118 472 LELEVAVEALARLQQGVSATVAHLLDLAGsagatGSWRSPSEPqEPLVQDLQAAVAAVQSAVHELLEFARSAVGNAAHTS 551
Cdd:cd11552    1 LDLEAAMETLARLQQGVSSSVSHLMSFIG-----GNWRSPEHM-EANVQDIHAAVEGVHGAVRELLEFARGAVSNAAQAS 74

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 282398118 552 DRALHAKLSRQLQKMEDVHQTLVAHGQALDAGRGGSGA------TLEDLDRLVACSRAVPEDAKQLASFLHGNASLLFRR 625
Cdd:cd11552   75 DRTLHAKLSRQLQKMEEVYQTLVRHSQALDACRWSPAAlaapgpTLDDLDRLVMYSRGVPDDAKQLASFLHGNASLLFRR 154

                 ...
gi 282398118 626 TKA 628
Cdd:cd11552  155 TKA 157

C-terminal FAT-like Four helix bundle domain, also called DUF3513, of CAS (Crk-Associated Substrate) scaffolding protein, Neural precursor cell Expressed, Developmentally Down-regulated 9; a protein interaction module; NEDD9 is also called human enhancer of filamentation 1 (HEF1) or CAS-L (Crk-associated substrate in lymphocyte). It was first described as a gene predominantly expressed in early embryonic brain, and was also isolated from a screen of human proteins that regulate filamentous budding in yeast, and as a tyrosine phosphorylated protein in lymphocytes. It promotes metastasis in different solid tumors. NEDD9 localizes in focal adhesions and associates with FAK and Abl kinase. It also interacts with SMAD3 and the proteasomal machinery which allows its rapid turnover; these interactions are not shared by other CAS proteins. CAS proteins function as molecular scaffolds to regulate protein complexes that are involved in many cellular processes. They share a common domain structure containing protein interaction modules that enable their scaffolding function, including an N-terminal SH3 domain, an unstructured substrate domain that contains many YxxP motifs, a serine-rich four-helix bundle, and a FAT-like C-terminal domain, which binds to the C-terminal domain of NSPs (novel SH2-containing proteins) to form multidomain signaling modules that mediate cell migration and invasion.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 282398118 758 DRQLLLFYLEQCEANLTTLTNAVDAFFTAVATNQPPKIFVAHSKFVILSAHKLVFIGDTLSRQAKAADVRSQVTHYSNLL 837
Cdd:cd11570    1 DRQLLGFYADQCETHFISLLNAIDAFFSCVSSGQPPRIFVAHSKFVILSAHKLVFIGDTLTRQVTVQDIRNRVMNSSNQL 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*...
gi 282398118 838 CDLLRGIVATTKAAALQYPSPSAAQDMVERVKELGHSTQQFRRVLGQL 885
Cdd:cd11570   81 CELLKTIVMATKMAALHYPSTAALQEMVDRVTDLSHLAQLFKLSLSQM 128

C-terminal FAT-like Four helix bundle domain, also called DUF3513, of CAS (Crk-Associated Substrate) scaffolding protein, Embryonal Fyn-associated Substrate; a protein interaction module; EFS is also called HEFS, CASS3 (CAS scaffolding protein family member 3) or SIN (Src-interacting protein). It was identified based on interactions with the Src kinases, Fyn and Yes. It plays a role in thymocyte development and acts as a negative regulator of T cell proliferation. CAS proteins function as molecular scaffolds to regulate protein complexes that are involved in many cellular processes. They share a common domain structure containing protein interaction modules that enable their scaffolding function, including an N-terminal SH3 domain, an unstructured substrate domain that contains many YxxP motifs, a serine-rich four-helix bundle, and a FAT-like C-terminal domain, which binds to the C-terminal domain of NSPs (novel SH2-containing proteins) to form multidomain signaling modules that mediate cell migration and invasion.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 282398118 758 DRQLLLFYLEQCEANLTTLTNAVDAFFTAVATNQPPKIFVAHSKFVILSAHKLVFIGDTLSRQAKAADVRSQVTHYSNLL 837
Cdd:cd11571    2 DSQLLHFYAGQCQSHYSTLLAAVAALLSSTQANQPPRVFVPHGKRLIVAAHKLVFVGDTLGRLASSAPLRARVATAGGAL 81

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*....
gi 282398118 838 CDLLRGIVATTKAAALQYPSPSAAQDMVERVKELGHSTQQFRRVLGQLA 886
Cdd:cd11571   82 CQALKAVVLATKGAALGYPSPPAAQEMAQCVADLSGQALQFTTLLQSLA 130

Src homology 3 domain of CAS (Crk-Associated Substrate) scaffolding proteins; CAS proteins function as molecular scaffolds to regulate protein complexes that are involved in many cellular processes including migration, chemotaxis, apoptosis, differentiation, and progenitor cell function. They mediate the signaling of integrins at focal adhesions where they localize, and thus, regulate cell invasion and survival. Over-expression of these proteins is implicated in poor prognosis, increased metastasis, and resistance to chemotherapeutics in many cancers such as breast, lung, melanoma, and glioblastoma. CAS proteins have also been linked to the pathogenesis of inflammatory disorders, Alzheimer's, Parkinson's, and developmental defects. They share a common domain structure that includes an N-terminal SH3 domain, an unstructured substrate domain that contains many YxxP motifs, a serine-rich four-helix bundle, and a FAT-like C-terminal domain. Vertebrates contain four CAS proteins: BCAR1 (or p130Cas), NEDD9 (or HEF1), EFS (or SIN), and CASS4 (or HEPL). The SH3 domain of CAS proteins binds to diverse partners including FAK, FRNK, Pyk2, PTP-PEST, DOCK180, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 282398118   7 LAKALYDNVAESPDELSFRKGDIMTVLEQDTQGLDGWWLCSLHGRQGIVPGNRLKI 62
Cdd:cd11844    1 LARALYDNVAESPDELAFRRGDILTVLEQNTAGLEGWWLCSLRGRQGIAPGNRLKL 56

C-terminal FAT-like Four helix bundle domain, also called DUF3513, of CAS (Crk-Associated Substrate) scaffolding protein family member 4; a protein interaction module; CASS4, also called HEPL (HEF1-EFS-p130Cas-like), localizes to focal adhesions and plays a role in regulating FAK activity, focal adhesion integrity, and cell spreading. It is most abundant in blood cells and lung tissue, and is also found in high levels in leukemia and ovarian cell lines. CAS proteins function as molecular scaffolds to regulate protein complexes that are involved in many cellular processes. They share a common domain structure containing protein interaction modules that enable their scaffolding function, including an N-terminal SH3 domain, an unstructured substrate domain that contains many YxxP motifs, a serine-rich four-helix bundle, and a FAT-like C-terminal domain, which binds to the C-terminal domain of NSPs (novel SH2-containing proteins) to form multidomain signaling modules that mediate cell migration and invasion.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 282398118 767 EQCEANLTTLTNAVDAFFTAVATNQPPKIFVAHSKFVILSAHKLVfigDTLSRQAKAADVRSQVTHYSNLLCDLLRGIVA 846
Cdd:cd11568   10 EHCRLYFGALQKAISVFHSSLSSNQPPEVFISHSKLIIMVGQKLV---DTLCQEAKEREARNEILAGSSQLCALLKNLAL 86

                         90       100       110
                 ....*....|....*....|....*....|....*..
gi 282398118 847 TTKAAALQYPSPSAAQDMVERVKELGHSTQQFRRVLG 883
Cdd:cd11568   87 ATKNAALQYPSPAALRELQDIADELAKHTQQFRAMLE 123

Serine rich Four helix bundle domain of CAS (Crk-Associated Substrate) scaffolding protein, Neural precursor cell Expressed, Developmentally Down-regulated 9; a protein interaction module; NEDD9 is also called human enhancer of filamentation 1 (HEF1) or CAS-L (Crk-associated substrate in lymphocyte). It was first described as a gene predominantly expressed in early embryonic brain, and was also isolated from a screen of human proteins that regulate filamentous budding in yeast, and as a tyrosine phosphorylated protein in lymphocytes. It promotes metastasis in different solid tumors. NEDD9 localizes in focal adhesions and associates with FAK and Abl kinase. It also interacts with SMAD3 and the proteasomal machinery which allows its rapid turnover; these interactions are not shared by other CAS proteins. CAS proteins function as molecular scaffolds to regulate protein complexes that are involved in many cellular processes. They share a common domain structure containing protein interaction modules that enable their scaffolding function, including an N-terminal SH3 domain, an unstructured substrate domain that contains many YxxP motifs, a serine-rich four-helix bundle, and a FAT-like C-terminal domain. CAS proteins associate with the 14-3-3 family; this interaction is regulated by integrin-mediated cell adhesion. The serine rich four helix bundle domain of BCAR1, another CAS protein, has been shown to bind 14-3-3 in a phosphorylation-dependent manner. This domain is structurally similar to other helical bundles found in cell adhesion components such as alpha-catenin, vinculin, and FAK, and may bind other proteins in addition to the 14-3-3 family.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 282398118 472 LELEVAVEALARLQQGVSATVAHLLDLAgsagaTGSWRSPSEpQEPLVQDLQAAVAAVQSAVHELLEFARSAVGNAAHTS 551
Cdd:cd11550    4 LDPDTAIERLYRLQQAVESSVSNLMALV-----SPDWRTYSF-MERHINEIRTAVDRVELSLGEYLQFGKGAAANATALS 77

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 282398118 552 DRALHAKLSRQLQKMEDVHQTLVAHGQALDA--------GRGGSGATLEDLDRLVACSRAVPEDAKQLASFLHGNASLLF 623
Cdd:cd11550   78 ENGLHNKMRRELQRLEDSHQILLQTYQDLNScnwslnilAANGHHNKCDDLDRFVMVAKTVPDDAKQLTTTIGSNAELLF 157

                 ...
gi 282398118 624 RRT 626
Cdd:cd11550  158 RRA 160

Serine rich Four helix bundle domain of CAS (Crk-Associated Substrate) scaffolding protein family member 4; a protein interaction module; CASS4, also called HEPL (HEF1-EFS-p130Cas-like), localizes to focal adhesions and plays a role in regulating FAK activity, focal adhesion integrity, and cell spreading. It is most abundant in blood cells and lung tissue, and is also found in high levels in leukemia and ovarian cell lines. CAS proteins function as molecular scaffolds to regulate protein complexes that are involved in many cellular processes. They share a common domain structure containing protein interaction modules that enable their scaffolding function, including an N-terminal SH3 domain, an unstructured substrate domain that contains many YxxP motifs, a serine-rich four-helix bundle, and a FAT-like C-terminal domain. CAS proteins associate with the 14-3-3 family; this interaction is regulated by integrin-mediated cell adhesion. The serine rich four helix bundle domain of BCAR1, another CAS protein, has been shown to bind 14-3-3 in a phosphorylation-dependent manner. This domain is structurally similar to other helical bundles found in cell adhesion components such as alpha-catenin, vinculin, and FAK, and may bind other proteins in addition to the 14-3-3 family.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 282398118 472 LELEVAVEALARLQQGVSATVAHLLDLAGSagatgSWRSpsepQEPLVQDLQA---AVAAVQSAVHELLEFARSAVGNAA 548
Cdd:cd11551    1 LDLEEAIETLTELQHAVSSSVASLMLFVSS-----KWRL----REHLEANLDQihrASDHITDSLDEFLDFARDVRGNAS 71

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 282398118 549 HTSDRALHAKLSRQLQKMEDVHQTLVAHGQALDaGRGGSGATL---------EDLDRLVACSRAVPEDAKQLASFLHGNA 619
Cdd:cd11551   72 RLTDSNLQTRIKKQLQILEDSFQILQETAEALD-NCNWSLEVLvddkpsqmpDDLERFVMVARTIPEDIKRFVSIIIANG 150

                 ....*.
gi 282398118 620 SLLFRR 625
Cdd:cd11551  151 KLLFRK 156

Src Homology 3 domain superfamily; Src Homology 3 (SH3) domains are protein interaction domains that bind proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. Thus, they are referred to as proline-recognition domains (PRDs). SH3 domains are less selective and show more diverse specificity compared to other PRDs. They have been shown to bind peptide sequences that lack the PxxP motif; examples include the PxxDY motif of Eps8 and the RKxxYxxY sequence in SKAP55. SH3 domain containing proteins play versatile and diverse roles in the cell, including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies, among others. Many members of this superfamily are adaptor proteins that associate with a number of protein partners, facilitating complex formation and signal transduction.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|..
gi 282398118   8 AKALYDNVAESPDELSFRKGDIMTVLEQDTqglDGWWLCSLH-GRQGIVPGN 58
Cdd:cd00174    2 ARALYDYEAQDDDELSFKKGDIITVLEKDD---DGWWEGELNgGREGLFPAN 50

SH3 domain; SH3 (Src homology 3) domains are often indicative of a protein involved in signal transduction related to cytoskeletal organization. First described in the Src cytoplasmic tyrosine kinase. The structure is a partly opened beta barrel.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 282398118    9 KALYDNVAESPDELSFRKGDIMTVLEQDTqglDGWWLCSLH-GRQGIVP 56
Cdd:pfam00018   1 VALYDYTAQEPDELSFKKGDIIIVLEKSE---DGWWKGRNKgGKEGLIP 46

Second C-terminal Src homology 3 domain of Dynamin Binding Protein, also called Tuba, and similar domains; DNMBP or Tuba is a cdc42-specific guanine nucleotide exchange factor (GEF) that contains four N-terminal SH3 domains, a central RhoGEF [or Dbl homology (DH)] domain followed by a Bin/Amphiphysin/Rvs (BAR) domain, and two C-terminal SH3 domains. It provides a functional link between dynamin, Rho GTPase signaling, and actin dynamics. It plays an important role in regulating cell junction configuration. The C-terminal SH3 domains of DNMBP bind to N-WASP and Ena/VASP proteins, which are key regulatory proteins of the actin cytoskeleton. Also included in this subfamily is the second C-terminal SH3 domain of Rho guanine nucleotide exchange factor 37 (ARHGEF37), whose function is still unknown. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|..
gi 282398118  10 ALYDNVAESPDELSFRKGDIMTVLE-QDTQGLDGWWLCSLHGRQGIVPGNRL 60
Cdd:cd11800    4 ALYTFEARSPGELSVTEGQVVTVLEkHDLKGNPEWWLVEDRGKQGYVPSNYL 55

Src Homology 3 domain of metazoan osteoclast stimulating factor 1; OSTF1, also named OSF or SH3P2, is a signaling protein containing SH3 and ankyrin-repeat domains. It acts through a Src-related pathway to enhance the formation of osteoclasts and bone resorption. It also acts as a negative regulator of cell motility. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|
gi 282398118   9 KALYDNVAESPDELSFRKGDIMTVLEQDTqglDGWWLCSLHGRQGIVPGN 58
Cdd:cd11772    3 RALYDYEAQHPDELSFEEGDLLYISDKSD---PNWWKATCGGKTGLIPSN 49

Src homology 3 domains of the p47phox subunit of NADPH oxidase and similar domains; This family is composed of the tandem SH3 domains of p47phox subunit of NADPH oxidase and Nox Organizing protein 1 (NoxO1), the four SH3 domains of Tks4 (Tyr kinase substrate with four SH3 domains), the five SH3 domains of Tks5, the SH3 domain of obscurin, Myosin-I, and similar domains. Most members of this group also contain Phox homology (PX) domains, except for obscurin and Myosin-I. p47phox and NoxO1 are regulators of the phagocytic NADPH oxidase complex (also called Nox2 or gp91phox) and nonphagocytic NADPH oxidase Nox1, respectively. They play roles in the activation of their respective NADPH oxidase, which catalyzes the transfer of electrons from NADPH to molecular oxygen to form superoxide. Tks proteins are Src substrates and scaffolding proteins that play important roles in the formation of podosomes and invadopodia, the dynamic actin-rich structures that are related to cell migration and cancer cell invasion. Obscurin is a giant muscle protein that plays important roles in the organization and assembly of the myofibril and the sarcoplasmic reticulum. Type I myosins (Myosin-I) are actin-dependent motors in endocytic actin structures and actin patches. They play roles in membrane traffic in endocytic and secretory pathways, cell motility, and mechanosensing. Myosin-I contains an N-terminal actin-activated ATPase, a phospholipid-binding TH1 (tail homology 1) domain, and a C-terminal extension which includes an F-actin-binding TH2 domain, an SH3 domain, and an acidic peptide that participates in activating the Arp2/3complex. The SH3 domain of myosin-I is required for myosin-I-induced actin polymerization. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|..
gi 282398118  10 ALYDNVAESPDELSFRKGDIMTVLEQDtqgLDGWWLCSLHGRQGIVPGNRLK 61
Cdd:cd11856    4 AIADYEAQGDDEISLQEGEVVEVLEKN---DSGWWYVRKGDKEGWVPASYLE 52

C-terminal Src homology 3 domain of Growth factor receptor-bound protein 2 (GRB2) and related proteins; This family includes the adaptor protein GRB2 and related proteins including Drosophila melanogaster Downstream of receptor kinase (DRK), Caenorhabditis elegans Sex muscle abnormal protein 5 (Sem-5), GRB2-related adaptor protein (GRAP), GRAP2, and similar proteins. Family members contain an N-terminal SH3 domain, a central SH2 domain, and a C-terminal SH3 domain. GRB2/Sem-5/DRK is a critical signaling molecule that regulates the Ras pathway by linking tyrosine kinases to the Ras guanine nucleotide releasing protein Sos (son of sevenless), which converts Ras to the active GTP-bound state. GRAP2 plays an important role in T cell receptor (TCR) signaling by promoting the formation of the SLP-76:LAT complex, which couples the TCR to the Ras pathway. GRAP acts as a negative regulator of T cell receptor (TCR)-induced lymphocyte proliferation by downregulating the signaling to the Ras/ERK pathway. The C-terminal SH3 domains (SH3c) of GRB2 and GRAP2 have been shown to bind to classical PxxP motif ligands, as well as to non-classical motifs. GRB2 SH3c binds Gab2 (Grb2-associated binder 2) through epitopes containing RxxK motifs, while the SH3c of GRAP2 binds to the phosphatase-like protein HD-PTP via a RxxxxK motif. SH3 domains are protein interaction domains that typically bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|..
gi 282398118   7 LAKALYDNVAESPDELSFRKGDIMTVLEQDTQgldGWWLCSLHGRQGIVPGN 58
Cdd:cd11805    1 RVQALYDFNPQEPGELEFRRGDIITVLDSSDP---DWWKGELRGRVGIFPAN 49

Src homology 3 domain of Myosins Ie, If, and similar proteins; Myosins Ie (MyoIe) and If (MyoIf) are nonmuscle, unconventional, long tailed, class I myosins containing an N-terminal motor domain and a myosin tail with TH1, TH2, and SH3 domains. MyoIe interacts with the endocytic proteins, dynamin and synaptojanin-1, through its SH3 domain; it may play a role in clathrin-dependent endocytosis. In the kidney, MyoIe is critical for podocyte function and normal glomerular filtration. Mutations in MyoIe is associated with focal segmental glomerulosclerosis, a disease characterized by massive proteinuria and progression to end-stage kidney disease. MyoIf is predominantly expressed in the immune system; it plays a role in immune cell motility and innate immunity. Mutations in MyoIf may be associated with the loss of hearing. The MyoIf gene has also been found to be fused to the MLL (Mixed lineage leukemia) gene in infant acute myeloid leukemias (AML). SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|.
gi 282398118   8 AKALYDNVAESPDELSFRKGDIMTVLEQDTQgldGWWLCSLHGRQGIVPGN 58
Cdd:cd11827    2 CKALYAYDAQDTDELSFNEGDIIEILKEDPS---GWWTGRLRGKEGLFPGN 49

Variant SH3 domain;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 282398118   10 ALYDNVAESPDELSFRKGDIMTVLEQDTqglDGWWLCSLHGRQGIVPGNRLK 61
Cdd:pfam14604   1 ALYPYEPKDDDELSLQRGDVITVIEESE---DGWWEGINTGRTGLVPANYVE 49

Src Homology 3 domain of Mixed Lineage Kinase 4; MLK4 is a Serine/Threonine Kinase (STK), catalyzing the transfer of the gamma-phosphoryl group from ATP to S/T residues on protein substrates. MLKs 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. MLKs play roles in immunity and inflammation, as well as in cell death, proliferation, and cell cycle regulation. The specific function of MLK4 is yet to be determined. Mutations in the kinase domain of MLK4 have been detected in colorectal cancers. MLK4 contains 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. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....
gi 282398118   7 LAKALYDNVAESPDELSFRKGDIMTVLEQD--TQGLDGWWLCSLHGRQGIVPGN 58
Cdd:cd12058    1 LWTALYDYEASGEDELSLRRGDVVEVLSQDaaVSGDDGWWAGKIRHRLGIFPAN 54

Src homology 3 domain of RUN and SH3 domain-containing proteins 1 and 2; RUSC1 and RUSC2, that were originally characterized in silico. They are adaptor proteins consisting of RUN, leucine zipper, and SH3 domains. RUSC1, also called NESCA (New molecule containing SH3 at the carboxy-terminus), is highly expressed in the brain and is translocated to the nuclear membrane from the cytoplasm upon stimulation with neurotrophin. It plays a role in facilitating neurotrophin-dependent neurite outgrowth. It also interacts with NEMO (or IKKgamma) and may function in NEMO-mediated activation of NF-kB. RUSC2, also called Iporin, is expressed ubiquitously with highest amounts in the brain and testis. It interacts with the small GTPase Rab1 and the Golgi matrix protein GM130, and may function in linking GTPases to certain intracellular signaling pathways. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*...
gi 282398118   9 KALYDNVAESPDELSFRKGDIMTVLeqdTQGLDGWWLCSLHGRQGIVP 56
Cdd:cd11810    3 RALCHHVATDSGQLSFRKGDILRVI---ARVDDDWLLCTRGSTKGLVP 47

Src homology 3 domain of Abl Interactor proteins; Abl interactor (Abi) proteins are adaptor proteins serving as binding partners and substrates of Abl tyrosine kinases. They are involved in regulating actin cytoskeletal reorganization and play important roles in membrane-ruffling, endocytosis, cell motility, and cell migration. They localize to sites of actin polymerization in epithelial adherens junction and immune synapses, as well as to the leading edge of lamellipodia. Vertebrates contain two Abi proteins, Abi1 and Abi2. Abi1 displays a wide expression pattern while Abi2 is highly expressed in the eye and brain. Abi proteins contain a homeobox homology domain, a proline-rich region, and a SH3 domain. The SH3 domain of Abi binds to a PxxP motif in Abl. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|
gi 282398118   9 KALYDNVAESPDELSFRKGDIMTVLEQDTqglDGWWLCSLHGRQGIVPGN 58
Cdd:cd11826    3 VALYDYTADKDDELSFQEGDIIYVTKKND---DGWYEGVLNGVTGLFPGN 49

Src Homology 3 domain of Sorting Nexin 9 and similar proteins; Sorting nexins (SNXs) are Phox homology (PX) domain containing proteins that are involved in regulating membrane traffic and protein sorting in the endosomal system. SNXs differ from each other in their lipid-binding specificity, subcellular localization and specific function in the endocytic pathway. This subfamily consists of SH3 domain containing SNXs including SNX9, SNX18, SNX33, and similar proteins. SNX9 is localized to plasma membrane endocytic sites and acts primarily in clathrin-mediated endocytosis, while SNX18 is localized to peripheral endosomal structures, and acts in a trafficking pathway that is clathrin-independent but relies on AP-1 and PACS1. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|.
gi 282398118   7 LAKALYDNVAESPDELSFRKGDIMTVLEQDTQglDGWWL-CSLHGRQGIVP 56
Cdd:cd11763    1 KVRALYDFDSQPSGELSLRAGEVLTITRQDVG--DGWLEgRNSRGEVGLFP 49

Fifth Src homology 3 domain of ADAM-binding protein Eve-1; Eve-1, also called SH3 domain-containing protein 19 (SH3D19) or EEN-binding protein (EBP), exists in multiple alternatively spliced isoforms. The longest isoform contains five SH3 domain in the C-terminal region and seven proline-rich motifs in the N-terminal region. It is abundantly expressed in skeletal muscle and heart, and may be involved in regulating the activity of ADAMs (A disintegrin and metalloproteases). Eve-1 interacts with EEN, an endophilin involved in endocytosis and may be the target of the MLL-EEN fusion protein that is implicated in leukemogenesis. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|.
gi 282398118   8 AKALYDNVAESPDELSFRKGDIMTVLEQDTqglDGWWLCSLHGRQGIVPGN 58
Cdd:cd11818    2 ARALYDFTGENEDELSFKAGDIITELESID---EEWMSGELRGKSGIFPKN 49

Third Src Homology 3 domain (SH3C) of Cbl-interacting protein of 85 kDa; CIN85, also called SH3 domain-containing kinase-binding protein 1 (SH3KBP1) or CD2-binding protein 3 (CD2BP3) or Ruk, is an adaptor protein that is involved in the downregulation of receptor tyrosine kinases by facilitating endocytosis through interaction with endophilin-associated ubiquitin ligase Cbl proteins. It is also important in many other cellular processes including vesicle-mediated transport, cytoskeletal remodelling, apoptosis, cell adhesion and migration, and viral infection, among others. CIN85 exists as multiple variants from alternative splicing; the main variant contains three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CIN85 to bind various protein partners and assemble complexes that have been implicated in many different functions. This alignment model represents the third SH3 domain (SH3C) of CIN85. SH3C has been shown to bind ubiquitin. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 282398118   9 KALYDNVAESPDELSFRKGDIMTVLEQDTQGLdGWWLCSLHGRQGIVPGNRLKIL 63
Cdd:cd12057    3 KVLFPYEAQNEDELTIKEGDIVTLISKDCIDA-GWWEGELNGRRGVFPDNFVKLL 56

Src homology 3 domain of Src kinase-like Protein Tyrosine Kinases; Src subfamily members include Src, Lck, Hck, Blk, Lyn, Fgr, Fyn, Yrk, Yes, and Brk. 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). However, Brk lacks the N-terminal myristoylation sites. 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, Lyn, and Brk show a limited expression pattern. This subfamily also includes Drosophila Src42A, Src oncogene at 42A (also known as Dsrc41) which accumulates at sites of cell-cell or cell-matrix adhesion, and participates in Drosphila development and wound healing. It has been shown to promote tube elongation in the tracheal system, is essential for proper cell-cell matching during dorsal closure, and regulates cell-cell contacts in developing Drosophila eyes. The SH3 domain of Src kinases contributes to substrate recruitment by binding adaptor proteins/substrates, and regulation of kinase activity through an intramolecular interaction. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|
gi 282398118  10 ALYDNVAESPDELSFRKGDIMTVLEqDTQGlDGWWLCSLH-GRQGIVPGN 58
Cdd:cd11845    4 ALYDYEARTDDDLSFKKGDRLQILD-DSDG-DWWLARHLStGKEGYIPSN 51

Src Homology 3 domain of Mixed Lineage Kinases 1, 2, and 3; MLKs 1, 2, and 3 are Serine/Threonine Kinases (STKs), catalyzing the transfer of the gamma-phosphoryl group from ATP to S/T residues on protein substrates. MLKs 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. MLKs play roles in immunity and inflammation, as well as in cell death, proliferation, and cell cycle regulation. Little is known about the specific function of MLK1, also called MAP3K9. 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. MLK2, also called MAP3K10, is abundant in brain, skeletal muscle, and testis. It functions upstream of the MAPK, c-Jun N-terminal kinase. It binds hippocalcin, a calcium-sensor protein that protects neurons against calcium-induced cell death. Both MLK2 and hippocalcin may be associated with the pathogenesis of Parkinson's disease. MLK3, also called MAP3K11, 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. It also functions as a negative regulator of Inhibitor of Nuclear Factor-KappaB Kinase (IKK) and thus, impacts inflammation and immunity. MLKs 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. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|.
gi 282398118  10 ALYDNVAESPDELSFRKGDIMTVLEQDTQ--GLDGWWLCSLHGRQGIVPGN 58
Cdd:cd12059    4 AVFDYEASAEDELTLRRGDRVEVLSKDSAvsGDEGWWTGKINDRVGIFPSN 54

Src homology 3 domain of Cortactin and related proteins; This subfamily includes cortactin, Abp1 (actin-binding protein 1), hematopoietic lineage cell-specific protein 1 (HS1), and similar proteins. These proteins are involved in regulating actin dynamics through direct or indirect interaction with the Arp2/3 complex, which is required to initiate actin polymerization. They all contain at least one C-terminal SH3 domain. Cortactin and HS1 bind Arp2/3 and actin through an N-terminal region that contains an acidic domain and several copies of a repeat domain found in cortactin and HS1. Abp1 binds actin via an N-terminal actin-depolymerizing factor (ADF) homology domain. Yeast Abp1 binds Arp2/3 directly through two acidic domains. Mammalian Abp1 does not directly interact with Arp2/3; instead, it regulates actin dynamics indirectly by interacting with dynamin and WASP family proteins. The C-terminal region of these proteins acts as an adaptor or scaffold that can connect membrane trafficking and signaling proteins that bind the SH3 domain within the actin network. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*...
gi 282398118   8 AKALYDNVAESPDELSFRKGDIMTVLEQ-DtqglDGWWL--CSlHGRQGIVPGNRLKI 62
Cdd:cd11819    2 AKALYDYQAAEDNEISFVEGDIITQIEQiD----EGWWLgvNA-KGQKGLFPANYVEL 54

Second Src Homology 3 domain of Nck adaptor proteins; Nck adaptor proteins regulate actin cytoskeleton dynamics by linking proline-rich effector molecules to protein tyrosine kinases and phosphorylated signaling intermediates. They contain three SH3 domains and a C-terminal SH2 domain. They function downstream of the PDGFbeta receptor and are involved in Rho GTPase signaling and actin dynamics. Vertebrates contain two Nck adaptor proteins: Nck1 (also called Nckalpha) and Nck2 (also called Nckbeta or Growth factor receptor-bound protein 4, Grb4), which show partly overlapping functions but also bind distinct targets. Their SH3 domains are involved in recruiting downstream effector molecules, such as the N-WASP/Arp2/3 complex, which when activated induces actin polymerization that results in the production of pedestals, or protrusions of the plasma membrane. The second SH3 domain of Nck appears to prefer ligands containing the APxxPxR motif. SH3 domains are protein interaction domains that usually bind to proline-rich ligands with moderate affinity and selectivity, preferentially a PxxP motif. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|.
gi 282398118   8 AKALYDNVAESPDELSFRKGDIMTVLEQDTqglDGWWLCSLHGRQGIVPGN 58
Cdd:cd11766    2 AVVKFNYEAQREDELSLRKGDRVLVLEKSS---DGWWRGECNGQVGWFPSN 49