RhoGAP_ARHGAP27_15_12_9: GTPase-activator protein (GAP) domain for Rho-like GTPases found in ARHGAP27 (also called CAMGAP1), ARHGAP15, 12 and 9-like proteins; This subgroup of ARHGAPs are multidomain proteins that contain RhoGAP, PH, SH3 and WW domains. Most members that are studied show GAP activity towards Rac1, some additionally show activity towards Cdc42. Small GTPases cluster into distinct families, and all act as molecular switches, active in their GTP-bound form but inactive when GDP-bound. The Rho family of GTPases activates effectors involved in a wide variety of developmental processes, including regulation of cytoskeleton formation, cell proliferation and the JNK signaling pathway. GTPases generally have a low intrinsic GTPase hydrolytic activity but there are family-specific groups of GAPs that enhance the rate of GTP hydrolysis by several orders of magnitude.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 187607956 638 FGCSLSSLCQRENSTVPRFVWLCIEQVEKNGLGVDGLYRVSGNLAIIQKLRFAVNHEEKIDLGDSKWEDIHVTTGALKMF 717
Cdd:cd04403    1 FGCHLEALCQRENSTVPKFVRLCIEAVEKRGLDVDGIYRVSGNLAVIQKLRFAVDHDEKLDLDDSKWEDIHVITGALKLF 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 187607956 718 FRELPEPLFTYTFFSDFISAIKMPDYKQKVQTVKDLMKKLPRPNHDTIQVLFKHLKKVIQHVDENRMTTQSVAIVFGPTL 797
Cdd:cd04403   81 FRELPEPLFPYSLFNDFVAAIKLSDYEQRVSAVKDLIKSLPKPNHDTLKMLFRHLCRVIEHGEKNRMTTQNLAIVFGPTL 160

                        170       180
                 ....*....|....*....|....*..
gi 187607956 798 LRPEIETANMAVHMVYQNQIVELILME 824
Cdd:cd04403  161 LRPEQETGNIAVHMVYQNQIVELILLE 187

Src Homology 3 domain of Rho GTPase-activating protein 12; Rho GTPase-activating proteins (RhoGAPs or ARHGAPs) bind to Rho proteins and enhance the hydrolysis rates of bound GTP. ARHGAP12 has been shown to display GAP activity towards Rac1. It plays a role in regulating hepatocyte growth factor (HGF)-driven cell growth and invasiveness. It contains SH3, WW, Pleckstin homology (PH), and RhoGAP domains. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 187607956  11 TYIEVEYDYDYKSKDRLITIKHGESYLLVKKTNDDWWQVRKDDASKPFYVPAQYVREVRR 70
Cdd:cd12070    1 TYIEVEYDYDYEAKDRKIVIKQGERYILVKKTNDDWWQVKKDENSKPFYVPAQYVKEVTR 60

WW domain; The WW domain is a protein module with two highly conserved tryptophans that binds proline-rich peptide motifs in vitro.

                          10        20
                  ....*....|....*....|....*..
gi 187607956  252 DWETHKDQNGRHYYYNRSTQERTWKPP 278
Cdd:pfam00397   4 GWEERWDPDGRVYYYNHETGETQWEKP 30

RhoGAP_ARHGAP27_15_12_9: GTPase-activator protein (GAP) domain for Rho-like GTPases found in ARHGAP27 (also called CAMGAP1), ARHGAP15, 12 and 9-like proteins; This subgroup of ARHGAPs are multidomain proteins that contain RhoGAP, PH, SH3 and WW domains. Most members that are studied show GAP activity towards Rac1, some additionally show activity towards Cdc42. Small GTPases cluster into distinct families, and all act as molecular switches, active in their GTP-bound form but inactive when GDP-bound. The Rho family of GTPases activates effectors involved in a wide variety of developmental processes, including regulation of cytoskeleton formation, cell proliferation and the JNK signaling pathway. GTPases generally have a low intrinsic GTPase hydrolytic activity but there are family-specific groups of GAPs that enhance the rate of GTP hydrolysis by several orders of magnitude.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 187607956 638 FGCSLSSLCQRENSTVPRFVWLCIEQVEKNGLGVDGLYRVSGNLAIIQKLRFAVNHEEKIDLGDSKWEDIHVTTGALKMF 717
Cdd:cd04403    1 FGCHLEALCQRENSTVPKFVRLCIEAVEKRGLDVDGIYRVSGNLAVIQKLRFAVDHDEKLDLDDSKWEDIHVITGALKLF 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 187607956 718 FRELPEPLFTYTFFSDFISAIKMPDYKQKVQTVKDLMKKLPRPNHDTIQVLFKHLKKVIQHVDENRMTTQSVAIVFGPTL 797
Cdd:cd04403   81 FRELPEPLFPYSLFNDFVAAIKLSDYEQRVSAVKDLIKSLPKPNHDTLKMLFRHLCRVIEHGEKNRMTTQNLAIVFGPTL 160

                        170       180
                 ....*....|....*....|....*..
gi 187607956 798 LRPEIETANMAVHMVYQNQIVELILME 824
Cdd:cd04403  161 LRPEQETGNIAVHMVYQNQIVELILLE 187

RhoGAP domain; GTPase activator proteins towards Rho/Rac/Cdc42-like small GTPases.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 187607956  654 PRFVWLCIEQVEKNGLGVDGLYRVSGNLAIIQKLRFAVNHEEKIDLgDSKWEDIHVTTGALKMFFRELPEPLFTYTFFSD 733
Cdd:pfam00620   1 PLIVRKCVEYLEKRGLDTEGIFRVSGSASRIKELREAFDRGPDVDL-DLEEEDVHVVASLLKLFLRELPEPLLTFELYEE 79

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 187607956  734 FISAIKMPDYKQKVQTVKDLMKKLPRPNHDTIQVLFKHLKKVIQHVDENRMTTQSVAIVFGPTLLRP 800
Cdd:pfam00620  80 FIEAAKLPDEEERLEALRELLRKLPPANRDTLRYLLAHLNRVAQNSDVNKMNAHNLAIVFGPTLLRP 146

Src Homology 3 domain of Rho GTPase-activating protein 12; Rho GTPase-activating proteins (RhoGAPs or ARHGAPs) bind to Rho proteins and enhance the hydrolysis rates of bound GTP. ARHGAP12 has been shown to display GAP activity towards Rac1. It plays a role in regulating hepatocyte growth factor (HGF)-driven cell growth and invasiveness. It contains SH3, WW, Pleckstin homology (PH), and RhoGAP domains. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 187607956  11 TYIEVEYDYDYKSKDRLITIKHGESYLLVKKTNDDWWQVRKDDASKPFYVPAQYVREVRR 70
Cdd:cd12070    1 TYIEVEYDYDYEAKDRKIVIKQGERYILVKKTNDDWWQVKKDENSKPFYVPAQYVKEVTR 60

WW domain; The WW domain is a protein module with two highly conserved tryptophans that binds proline-rich peptide motifs in vitro.

                          10        20
                  ....*....|....*....|....*..
gi 187607956  252 DWETHKDQNGRHYYYNRSTQERTWKPP 278
Cdd:pfam00397   4 GWEERWDPDGRVYYYNHETGETQWEKP 30

Two conserved tryptophans domain; also known as the WWP or rsp5 domain; around 40 amino acids; functions as an interaction module in a diverse set of signalling proteins; binds specific proline-rich sequences but at low affinities compared to other peptide recognition proteins such as antibodies and receptors; WW domains have a single groove formed by a conserved Trp and Tyr which recognizes a pair of residues of the sequence X-Pro; variable loops and neighboring domains confer specificity in this domain; there are five distinct groups based on binding: 1) PPXY motifs 2) the PPLP motif; 3) PGM motifs; 4) PSP or PTP motifs; 5) PR motifs.

                         10        20        30
                 ....*....|....*....|....*....|
gi 187607956 250 NGDWETHKDQNGRHYYYNRSTQERTWKPPR 279
Cdd:cd00201    1 PPGWEERWDPDGRVYYYNHNTKETQWEDPR 30

PH domain; PH stands for pleckstrin homology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 187607956  462 GKKVRKNWTSYWTVLQGSLLIFNKGQGggsgwfgRDQKSSVEYSVDLKGGSVDWASK-DKSSKKHVLELKT---RQGTEL 537
Cdd:pfam00169  11 GGGKKKSWKKRYFVLFDGSLLYYKDDK-------SGKSKEPKGSISLSGCEVVEVVAsDSPKRKFCFELRTgerTGKRTY 83

                          90       100
                  ....*....|....*....|..
gi 187607956  538 LLQSDSDGLVNDWHKALTEAIH 559
Cdd:pfam00169  84 LLQAESEEERKDWIKAIQSAIR 105

Domain with 2 conserved Trp (W) residues; Also known as the WWP or rsp5 domain. Binds proline-rich polypeptides.

                           10        20
                   ....*....|....*....|....*..
gi 187607956   253 WETHKDQNGRHYYYNRSTQERTWKPPR 279
Cdd:smart00456   6 WEERKDPDGRPYYYNHETKETQWEKPR 32

RhoGAP_ARHGAP27_15_12_9: GTPase-activator protein (GAP) domain for Rho-like GTPases found in ARHGAP27 (also called CAMGAP1), ARHGAP15, 12 and 9-like proteins; This subgroup of ARHGAPs are multidomain proteins that contain RhoGAP, PH, SH3 and WW domains. Most members that are studied show GAP activity towards Rac1, some additionally show activity towards Cdc42. Small GTPases cluster into distinct families, and all act as molecular switches, active in their GTP-bound form but inactive when GDP-bound. The Rho family of GTPases activates effectors involved in a wide variety of developmental processes, including regulation of cytoskeleton formation, cell proliferation and the JNK signaling pathway. GTPases generally have a low intrinsic GTPase hydrolytic activity but there are family-specific groups of GAPs that enhance the rate of GTP hydrolysis by several orders of magnitude.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 187607956 638 FGCSLSSLCQRENSTVPRFVWLCIEQVEKNGLGVDGLYRVSGNLAIIQKLRFAVNHEEKIDLGDSKWEDIHVTTGALKMF 717
Cdd:cd04403    1 FGCHLEALCQRENSTVPKFVRLCIEAVEKRGLDVDGIYRVSGNLAVIQKLRFAVDHDEKLDLDDSKWEDIHVITGALKLF 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 187607956 718 FRELPEPLFTYTFFSDFISAIKMPDYKQKVQTVKDLMKKLPRPNHDTIQVLFKHLKKVIQHVDENRMTTQSVAIVFGPTL 797
Cdd:cd04403   81 FRELPEPLFPYSLFNDFVAAIKLSDYEQRVSAVKDLIKSLPKPNHDTLKMLFRHLCRVIEHGEKNRMTTQNLAIVFGPTL 160

                        170       180
                 ....*....|....*....|....*..
gi 187607956 798 LRPEIETANMAVHMVYQNQIVELILME 824
Cdd:cd04403  161 LRPEQETGNIAVHMVYQNQIVELILLE 187

RhoGAP: GTPase-activator protein (GAP) for Rho-like GTPases; GAPs towards Rho/Rac/Cdc42-like small GTPases. Small GTPases (G proteins) cluster into distinct families, and all act as molecular switches, active in their GTP-bound form but inactive when bound to GDP. The Rho family of small G proteins, which includes Cdc42Hs, activates effectors involved in a wide variety of developmental processes, including regulation of cytoskeleton formation, cell proliferation and the JNK signaling pathway. G proteins generally have a low intrinsic GTPase hydrolytic activity but there are family-specific groups of GAPs that enhance the rate of GTP hydrolysis by several orders of magnitude. The RhoGAPs are one of the major classes of regulators of Rho G proteins.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 187607956 654 PRFVWLCIEQVEKNGLGVDGLYRVSGNLAIIQKLRFAVNHEEKIDlgDSKWEDIHVTTGALKMFFRELPEPLFTYTFFSD 733
Cdd:cd00159    1 PLIIEKCIEYLEKNGLNTEGIFRVSGSASKIEELKKKFDRGEDID--DLEDYDVHDVASLLKLYLRELPEPLIPFELYDE 78

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 187607956 734 FISAIKMPDYKQKVQTVKDLMKKLPRPNHDTIQVLFKHLKKVIQHVDENRMTTQSVAIVFGPTLLRPEIETANMAVHMVY 813
Cdd:cd00159   79 FIELAKIEDEEERIEALKELLKSLPPENRDLLKYLLKLLHKISQNSEVNKMTASNLAIVFAPTLLRPPDSDDELLEDIKK 158

                 ....*....
gi 187607956 814 QNQIVELIL 822
Cdd:cd00159  159 LNEIVEFLI 167

RhoGAP_ARHGAP21: RhoGAP (GTPase-activator protein [GAP] for Rho-like small GTPases) domain of ArhGAP21-like proteins. ArhGAP21 is a multi-domain protein, containing RhoGAP, PH and PDZ domains, and is believed to play a role in the organization of the cell-cell junction complex. It has been shown to function as a GAP of Cdc42 and RhoA, and to interact with alpha-catenin and Arf6. Small GTPases cluster into distinct families, and all act as molecular switches, active in their GTP-bound form but inactive when GDP-bound. The Rho family of GTPases activates effectors involved in a wide variety of developmental processes, including regulation of cytoskeleton formation, cell proliferation and the JNK signaling pathway. GTPases generally have a low intrinsic GTPase hydrolytic activity but there are family-specific groups of GAPs that enhance the rate of GTP hydrolysis by several orders of magnitude.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 187607956 637 VFGCSLSSlCQ--RENSTVPRFVWLCIEQVEKNGLGVDGLYRVSGNLAIIQKLRFAVNHE-EKIDLGDSKWEDIHVTTGA 713
Cdd:cd04395    1 TFGVPLDD-CPpsSENPYVPLIVEVCCNIVEARGLETVGIYRVPGNNAAISALQEELNRGgFDIDLQDPRWRDVNVVSSL 79

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 187607956 714 LKMFFRELPEPLFTYTFFSDFISAIKMPDYKQKVQTVKDLMKKLPRPNHDTIQVLFKHLKKVIQHVDENRMTTQSVAIVF 793
Cdd:cd04395   80 LKSFFRKLPEPLFTNELYPDFIEANRIEDPVERLKELRRLIHSLPDHHYETLKHLIRHLKTVADNSEVNKMEPRNLAIVF 159

                        170       180       190
                 ....*....|....*....|....*....|....*..
gi 187607956 794 GPTLLRPEIET-ANMAVHMVYQNQIVELILMEYDTIF 829
Cdd:cd04395  160 GPTLVRTSDDNmETMVTHMPDQCKIVETLIQHYDWFF 196

RhoGAP_chimaerin: RhoGAP (GTPase-activator protein [GAP] for Rho-like small GTPases) domain of chimaerins. Chimaerins are a family of phorbolester- and diacylglycerol-responsive GAPs specific for the Rho-like GTPase Rac. Chimaerins exist in two alternative splice forms that each contain a C-terminal GAP domain, and a central C1 domain which binds phorbol esters, inducing a conformational change that activates the protein; one splice form is lacking the N-terminal Src homology-2 (SH2) domain. Small GTPases cluster into distinct families, and all act as molecular switches, active in their GTP-bound form but inactive when GDP-bound. The Rho family of GTPases activates effectors involved in a wide variety of developmental processes, including regulation of cytoskeleton formation, cell proliferation and the JNK signaling pathway. GTPases generally have a low intrinsic GTPase hydrolytic activity but there are family-specific groups of GAPs that enhance the rate of GTP hydrolysis by several orders of magnitude.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 187607956 638 FGCSLSSLCQRENSTVPRFVWLCIEQVEKNGLGVDGLYRVSGNLAIIQKLRFAVNHE-EKIDLGDSKWEDIHVTTGALKM 716
Cdd:cd04372    1 YGCDLTTLVKAHNTQRPMVVDMCIREIEARGLQSEGLYRVSGFAEEIEDVKMAFDRDgEKADISATVYPDINVITGALKL 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 187607956 717 FFRELPEPLFTYTFFSDFISAIKMPDYKQKVQTVKDLMKKLPRPNHDTIQVLFKHLKKVIQHVDENRMTTQSVAIVFGPT 796
Cdd:cd04372   81 YFRDLPIPVITYDTYPKFIDAAKISNPDERLEAVHEALMLLPPAHYETLRYLMEHLKRVTLHEKDNKMNAENLGIVFGPT 160

                        170       180       190
                 ....*....|....*....|....*....|....
gi 187607956 797 LLRPEIETANMAVH-MVYQNQIVELILMEYDTIF 829
Cdd:cd04372  161 LMRPPEDSALTTLNdMRYQILIVQLLITNEDVLF 194

RhoGAP_myosin_IX: RhoGAP (GTPase-activator protein [GAP] for Rho-like small GTPases) domain present in class IX myosins. Class IX myosins contain a characteristic head domain, a neck domain, a tail domain which contains a C6H2-zinc binding motif and a RhoGAP domain. Class IX myosins are single-headed, processive myosins that are partly cytoplasmic, and partly associated with membranes and the actin cytoskeleton. Class IX myosins are implicated in the regulation of neuronal morphogenesis and function of sensory systems, like the inner ear. There are two major isoforms, myosin IXA and IXB with several splice variants, which are both expressed in developing neurons. Small GTPases cluster into distinct families, and all act as molecular switches, active in their GTP-bound form but inactive when GDP-bound. The Rho family of GTPases activates effectors involved in a wide variety of developmental processes, including regulation of cytoskeleton formation, cell proliferation and the JNK signaling pathway. GTPases generally have a low intrinsic GTPase hydrolytic activity but there are family-specific groups of GAPs that enhance the rate of GTP hydrolysis by several orders of magnitude.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 187607956 638 FGCSLSSLCQrENSTVPRFVWLCIEQVEKNGLGVDGLYRVSGNLAIIQKLRFAVNHE-EKIDLGDSKwedIHVTTGALKM 716
Cdd:cd04377    1 FGVSLSSLTS-EDRSVPLVLEKLLEHIEMHGLYTEGIYRKSGSANKIKELRQGLDTDpDSVNLEDYP---IHVITSVLKQ 76

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 187607956 717 FFRELPEPLFTYTFFSDFISAIKMPDYKQKVQTVKDLMKKLPRPNHDTIQVLFKHLKKVIQHVDENRMTTQSVAIVFGPT 796
Cdd:cd04377   77 WLRELPEPLMTFELYENFLRAMELEEKQERVRALYSVLEQLPRANLNTLERLIFHLVRVALQEEVNRMSANALAIVFAPC 156

                        170       180       190
                 ....*....|....*....|....*....|
gi 187607956 797 LLR-PEIETANMAVHMVY-QNQIVELILME 824
Cdd:cd04377  157 ILRcPDTADPLQSLQDVSkTTTCVETLIKE 186

Beta-spectrin pleckstrin homology (PH) domain; ARHGAP family genes encode Rho/Rac/Cdc42-like GTPase activating proteins with RhoGAP domain. The ARHGAP members here all have a PH domain upstream of their C-terminal RhoGAP domain. Some have additional N-terminal SH3 and WW domains. The members here include: ARHGAP9, ARHGAP12, ARHGAP15, and ARHGAP27. ARHGAP27 and ARHGAP12 shared the common-domain structure, consisting of SH3, WW, PH, and RhoGAP domains. The PH domain of ArhGAP9 employs a non-canonical phosphoinositide binding mechanism, a variation of the spectrin- Ins(4,5)P2-binding mode, that gives rise to a unique PI binding profile, namely a preference for both PI(4,5)P2 and the PI 3-kinase products PI(3,4,5)P3 and PI(3,4)P2. This lipid binding mechanism is also employed by the PH domain of Tiam1 and Slm1. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 187607956 448 EKCATLNMTKITEHGKKVRKNWTSYWTVLQGSLLIFNKgqgggsgwfgrDQKSSV---------EYSVDLKGGSVDWAsK 518
Cdd:cd13233    1 EKQGLLNKTKIAENGKKLRKNWSTSWVVLTSSHLLFYK-----------DAKSAAksgnpyskpESSVDLRGASIEWA-K 68

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|
gi 187607956 519 DKSSKKHVLELKTRQGTELLLQSDSDGLVNDWHKALTEAI 558
Cdd:cd13233   69 EKSSRKNVFQISTVTGTEFLLQSDNDTEIREWFDAIKAVI 108

RhoGAP_Bcr: RhoGAP (GTPase-activator protein [GAP] for Rho-like small GTPases) domain of Bcr (breakpoint cluster region protein)-like proteins. Bcr is a multidomain protein with a variety of enzymatic functions. It contains a RhoGAP and a Rho GEF domain, a Ser/Thr kinase domain, an N-terminal oligomerization domain, and a C-terminal PDZ binding domain, in addition to PH and C2 domains. Bcr is a negative regulator of: i) RacGTPase, via the Rho GAP domain, ii) the Ras-Raf-MEK-ERK pathway, via phosphorylation of the Ras binding protein AF-6, and iii) the Wnt signaling pathway through binding beta-catenin. Bcr can form a complex with beta-catenin and Tcf1. The Wnt signaling pathway is involved in cell proliferation, differentiation, and cell renewal. Bcr was discovered as a fusion partner of Abl. The Bcr-Abl fusion is characteristic for a large majority of chronic myelogenous leukemias (CML). Small GTPases cluster into distinct families, and all act as molecular switches, active in their GTP-bound form but inactive when GDP-bound. The Rho family of GTPases activates effectors involved in a wide variety of developmental processes, including regulation of cytoskeleton formation, cell proliferation and the JNK signaling pathway. GTPases generally have a low intrinsic GTPase hydrolytic activity but there are family-specific groups of GAPs that enhance the rate of GTP hydrolysis by several orders of magnitude.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 187607956 638 FGCSLSSLCQRENSTVPRFVWLCIEQVEKNGLGVDGLYRVSGNLAIIQKLRFAVNHEEKIDLGDSKWEDIHVTTGALKMF 717
Cdd:cd04387    1 FGVKISTVTKRERSKVPYIVRQCVEEVERRGMEEVGIYRISGVATDIQALKAAFDTNNKDVSVMLSEMDVNAIAGTLKLY 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 187607956 718 FRELPEPLFTYTFFSDFISAIKMPDYKQKVQTVKDLMKKLPRPNHDTIQVLFKHLKKVIQHVDENRMTTQSVAIVFGPTL 797
Cdd:cd04387   81 FRELPEPLFTDELYPNFAEGIALSDPVAKESCMLNLLLSLPDPNLVTFLFLLHHLKRVAEREEVNKMSLHNLATVFGPTL 160

                        170       180
                 ....*....|....*....|...
gi 187607956 798 LRPEIETANMAVHMVYQNQIVEL 820
Cdd:cd04387  161 LRPSEKESKIPTNTMTDSWSLEV 183

RhoGAP-p50rhoGAP: RhoGAP (GTPase-activator protein [GAP] for Rho-like small GTPases) domain of p50RhoGAP-like proteins; p50RhoGAP, also known as RhoGAP-1, contains a C-terminal RhoGAP domain and an N-terminal Sec14 domain which binds phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3). It is ubiquitously expressed and preferentially active on Cdc42. This subgroup also contains closely related ARHGAP8. Small GTPases cluster into distinct families, and all act as molecular switches, active in their GTP-bound form but inactive when GDP-bound. The Rho family of GTPases activates effectors involved in a wide variety of developmental processes, including regulation of cytoskeleton formation, cell proliferation and the JNK signaling pathway. GTPases generally have a low intrinsic GTPase hydrolytic activity but there are family-specific groups of GAPs that enhance the rate of GTP hydrolysis by several orders of magnitude.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 187607956 636 QVFGCSLSSLCQR--ENSTVPRFVWLCIEQVEKNGLGVDGLYRVSGNLAIIQKLRFAVNHEEKIDLGDskWEDIHVTTGA 713
Cdd:cd04404    4 QQFGVSLQFLKEKnpEQEPIPPVVRETVEYLQAHALTTEGIFRRSANTQVVKEVQQKYNMGEPVDFDQ--YEDVHLPAVI 81

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 187607956 714 LKMFFRELPEPLFTYTFFSDfISAIKMPDYKQKVQTVKDLMKKLPRPNHDTIQVLFKHLKKVIQHVDENRMTTQSVAIVF 793
Cdd:cd04404   82 LKTFLRELPEPLLTFDLYDD-IVGFLNVDKEERVERVKQLLQTLPEENYQVLKYLIKFLVQVSAHSDQNKMTNSNLAVVF 160

                        170       180       190
                 ....*....|....*....|....*....|....*.
gi 187607956 794 GPTLLRPEIETANMAVhMVYQNQIVELILMEYDTIF 829
Cdd:cd04404  161 GPNLLWAKDASMSLSA-INPINTFTKFLLDHQDEIF 195

Src Homology 3 domain of Rho GTPase-activating protein 12; Rho GTPase-activating proteins (RhoGAPs or ARHGAPs) bind to Rho proteins and enhance the hydrolysis rates of bound GTP. ARHGAP12 has been shown to display GAP activity towards Rac1. It plays a role in regulating hepatocyte growth factor (HGF)-driven cell growth and invasiveness. It contains SH3, WW, Pleckstin homology (PH), and RhoGAP domains. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 187607956  11 TYIEVEYDYDYKSKDRLITIKHGESYLLVKKTNDDWWQVRKDDASKPFYVPAQYVREVRR 70
Cdd:cd12070    1 TYIEVEYDYDYEAKDRKIVIKQGERYILVKKTNDDWWQVKKDENSKPFYVPAQYVKEVTR 60

Linker region between SH3 and WW domains on ARHGAP12; SH3-WW_linker is a natively unstructured region on Rho-GTPase activating factor 12 proteins that lies between the SH3 and the WW domains. it is found in higher eukaryotes, and the function is not known.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 187607956   67 EVRRALMPPPKPLniagrgGPAPNRPSALEI---QRPNDN-----------KKSPCPSPSS----TALLPPRDDRGSPVS 128
Cdd:pfam16618   1 EVRKALMPPPKPI------AHPNSPPKVLDIgplQRSTENlnkppelssfgRPSPSQTTSPsshfTPPALRRDANQNLGS 74

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 187607956  129 PTRHLPPA------------QMNTFPGSLPCFRAESP-GSKLDGERDKDKDSERkdrgekaavQEELAEEGgdSDKNRID 195
Cdd:pfam16618  75 PTDHEQSLaelllltnnngkFHHGSHSTLPRSRARSPsLGKFPGPEFLDVDKTE---------QCDSAGEG--SEKLRND 143

                         170       180       190
                  ....*....|....*....|....*....|....*....
gi 187607956  196 SESGDELSSGSTDNLQSLG-SGQGRPDSPVYTNLQEMKI 233
Cdd:pfam16618 144 SESGDELSSSSTEHLQPTSpSGQGRSDSPVYTNLQELKI 182

RhoGAP_MgcRacGAP: RhoGAP (GTPase-activator protein [GAP] for Rho-like small GTPases) domain present in MgcRacGAP proteins. MgcRacGAP plays an important dual role in cytokinesis: i) it is part of centralspindlin-complex, together with the mitotic kinesin MKLP1, which is critical for the structure of the central spindle by promoting microtuble bundling. ii) after phosphorylation by aurora B MgcRacGAP becomes an effective regulator of RhoA and plays an important role in the assembly of the contractile ring and the initiation of cytokinesis. MgcRacGAP-like proteins contain a N-terminal C1-like domain, and a C-terminal RhoGAP domain. Small GTPases cluster into distinct families, and all act as molecular switches, active in their GTP-bound form but inactive when GDP-bound. The Rho family of GTPases activates effectors involved in a wide variety of developmental processes, including regulation of cytoskeleton formation, cell proliferation and the JNK signaling pathway. GTPases generally have a low intrinsic GTPase hydrolytic activity but there are family-specific groups of GAPs that enhance the rate of GTP hydrolysis by several orders of magnitude.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 187607956 653 VPRFVWLCIEQVEKNGLGVDGLYRVSGNLAIIQKLRFAVNHEEKI-DLGDSkweDIHVTTGALKMFFRELPEPLFTYTFF 731
Cdd:cd04382   17 IPALIVHCVNEIEARGLTEEGLYRVSGSEREVKALKEKFLRGKTVpNLSKV---DIHVICGCLKDFLRSLKEPLITFALW 93

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 187607956 732 SDFISAIKMPDYKQKVQTVKDLMKKLPRPNHDTIQVLFKHLKKVIQhVDENRMTTQSVAIVFGPTL---LRPEIETANMA 808
Cdd:cd04382   94 KEFMEAAEILDEDNSRAALYQAISELPQPNRDTLAFLILHLQRVAQ-SPECKMDINNLARVFGPTIvgySVPNPDPMTIL 172

                        170
                 ....*....|....
gi 187607956 809 VHMVYQNQIVELIL 822
Cdd:cd04382  173 QDTVRQPRVVERLL 186

RhoGAP_ARHGAP18: RhoGAP (GTPase-activator protein [GAP] for Rho-like small GTPases) domain of ArhGAP18-like proteins. The function of ArhGAP18 is unknown. Small GTPases cluster into distinct families, and all act as molecular switches, active in their GTP-bound form but inactive when GDP-bound. The Rho family of GTPases activates effectors involved in a wide variety of developmental processes, including regulation of cytoskeleton formation, cell proliferation and the JNK signaling pathway. GTPases generally have a low intrinsic GTPase hydrolytic activity but there are family-specific groups of GAPs that enhance the rate of GTP hydrolysis by several orders of magnitude.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 187607956 637 VFGCSLSSLCQR-----ENSTVPRFVWLCIEQVEKNGLGVDGLYRVSGNLAIIQKLRFAVnhEEKIDLGDSKWEDIHV-- 709
Cdd:cd04391    1 LFGVPLSTLLERdqkkvPGSKVPLIFQKLINKLEERGLETEGILRIPGSAQRVKFLCQEL--EAKFYEGTFLWDQVKQhd 78

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 187607956 710 TTGALKMFFRELPEPLFTYTFFSDFISAIKMPDYKQKVQTVKDLMKKLPRPNHDTIQVLFKHLKKVIQHVDENRMTTQSV 789
Cdd:cd04391   79 AASLLKLFIRELPQPLLTVEYLPAFYSVQGLPSKKDQLQALNLLVLLLPEANRDTLKALLEFLQKVVDHEEKNKMNLWNV 158

                        170
                 ....*....|.
gi 187607956 790 AIVFGPTLLRP 800
Cdd:cd04391  159 AMIMAPNLFPP 169

RhoGAP_ARAP: RhoGAP (GTPase-activator protein [GAP] for Rho-like small GTPases) domain present in ARAPs. ARAPs (also known as centaurin deltas) contain, besides the RhoGAP domain, an Arf GAP, ankyrin repeat ras-associating, and PH domains. Since their ArfGAP activity is PIP3-dependent, ARAPs are considered integration points for phosphoinositide, Arf and Rho signaling. Small GTPases cluster into distinct families, and all act as molecular switches, active in their GTP-bound form but inactive when GDP-bound. The Rho family of GTPases activates effectors involved in a wide variety of developmental processes, including regulation of cytoskeleton formation, cell proliferation and the JNK signaling pathway. GTPases generally have a low intrinsic GTPase hydrolytic activity but there are family-specific groups of GAPs that enhance the rate of GTP hydrolysis by several orders of magnitude.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 187607956 653 VPRFVWLCIEQVEKNGLGVDGLYRVSGNLAIIQKLRFAVNHEE---KIDLGDskwEDIHVTTGALKMFFRELPEPLFTYT 729
Cdd:cd04385   15 IPVIVDKCIDFITQHGLMSEGIYRKNGKNSSVKKLLEAFRKDArsvQLREGE---YTVHDVADVLKRFLRDLPDPLLTSE 91

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 187607956 730 FFSDFISAIKMPDYKQKVQTVKDLMKKLPRPNHDTIQVLFKHLKKVIQHVDENRMTTQSVAIVFGPTLLRPEIETANMAV 809
Cdd:cd04385   92 LHAEWIEAAELENKDERIARYKELIRRLPPINRATLKVLIGHLYRVQKHSDENQMSVHNLALVFGPTLFQTDEHSVGQTS 171

                        170
                 ....*....|....*.
gi 187607956 810 HMVyqnQIVELILMEY 825
Cdd:cd04385  172 HEV---KVIEDLIDNY 184