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 1207147817 660 FGCSLSSLCQRENSTVPRFVWLCIEQVEKNGLGVDGLYRVSGNLAIIQKLRFAVNHEEKIDLGDSKWEDIHVTTGALKMF 739
Cdd:cd04403     1 FGCHLEALCQRENSTVPKFVRLCIEAVEKRGLDVDGIYRVSGNLAVIQKLRFAVDHDEKLDLDDSKWEDIHVITGALKLF 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207147817 740 FRELPEPLFTYTFFSDFISAIKMPDYKQKVQTVKDLMKKLPRPNHDTIQVLFKHLKKVIQHVDENRMTTQSVAIVFGPTL 819
Cdd:cd04403    81 FRELPEPLFPYSLFNDFVAAIKLSDYEQRVSAVKDLIKSLPKPNHDTLKMLFRHLCRVIEHGEKNRMTTQNLAIVFGPTL 160

                         170       180
                  ....*....|....*....|....*..
gi 1207147817 820 LRPEIETANMAVHMVYQNQIVELILME 846
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 1207147817  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 1207147817 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 1207147817 660 FGCSLSSLCQRENSTVPRFVWLCIEQVEKNGLGVDGLYRVSGNLAIIQKLRFAVNHEEKIDLGDSKWEDIHVTTGALKMF 739
Cdd:cd04403     1 FGCHLEALCQRENSTVPKFVRLCIEAVEKRGLDVDGIYRVSGNLAVIQKLRFAVDHDEKLDLDDSKWEDIHVITGALKLF 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207147817 740 FRELPEPLFTYTFFSDFISAIKMPDYKQKVQTVKDLMKKLPRPNHDTIQVLFKHLKKVIQHVDENRMTTQSVAIVFGPTL 819
Cdd:cd04403    81 FRELPEPLFPYSLFNDFVAAIKLSDYEQRVSAVKDLIKSLPKPNHDTLKMLFRHLCRVIEHGEKNRMTTQNLAIVFGPTL 160

                         170       180
                  ....*....|....*....|....*..
gi 1207147817 820 LRPEIETANMAVHMVYQNQIVELILME 846
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 1207147817 676 PRFVWLCIEQVEKNGLGVDGLYRVSGNLAIIQKLRFAVNHEEKIDLgDSKWEDIHVTTGALKMFFRELPEPLFTYTFFSD 755
Cdd:pfam00620   1 PLIVRKCVEYLEKRGLDTEGIFRVSGSASRIKELREAFDRGPDVDL-DLEEEDVHVVASLLKLFLRELPEPLLTFELYEE 79

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1207147817 756 FISAIKMPDYKQKVQTVKDLMKKLPRPNHDTIQVLFKHLKKVIQHVDENRMTTQSVAIVFGPTLLRP 822
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 1207147817  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 1207147817 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 1207147817 250 NGDWETHKDQNGRHYYYNRSTQERTWKPPR 279
Cdd:cd00201     1 PPGWEERWDPDGRVYYYNHNTKETQWEDPR 30

PH domain; PH stands for pleckstrin homology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207147817 484 GKKVRKNWTSYWTVLQGSLLIFNKGQGggsgwfgRDQKSSVEYSVDLKGGSVDWASK-DKSSKKHVLELKT---RQGTEL 559
Cdd:pfam00169  11 GGGKKKSWKKRYFVLFDGSLLYYKDDK-------SGKSKEPKGSISLSGCEVVEVVAsDSPKRKFCFELRTgerTGKRTY 83

                          90       100
                  ....*....|....*....|..
gi 1207147817 560 LLQSDSDGLVNDWHKALTEAIH 581
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 1207147817  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 1207147817 660 FGCSLSSLCQRENSTVPRFVWLCIEQVEKNGLGVDGLYRVSGNLAIIQKLRFAVNHEEKIDLGDSKWEDIHVTTGALKMF 739
Cdd:cd04403     1 FGCHLEALCQRENSTVPKFVRLCIEAVEKRGLDVDGIYRVSGNLAVIQKLRFAVDHDEKLDLDDSKWEDIHVITGALKLF 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207147817 740 FRELPEPLFTYTFFSDFISAIKMPDYKQKVQTVKDLMKKLPRPNHDTIQVLFKHLKKVIQHVDENRMTTQSVAIVFGPTL 819
Cdd:cd04403    81 FRELPEPLFPYSLFNDFVAAIKLSDYEQRVSAVKDLIKSLPKPNHDTLKMLFRHLCRVIEHGEKNRMTTQNLAIVFGPTL 160

                         170       180
                  ....*....|....*....|....*..
gi 1207147817 820 LRPEIETANMAVHMVYQNQIVELILME 846
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 1207147817 676 PRFVWLCIEQVEKNGLGVDGLYRVSGNLAIIQKLRFAVNHEEKIDlgDSKWEDIHVTTGALKMFFRELPEPLFTYTFFSD 755
Cdd:cd00159     1 PLIIEKCIEYLEKNGLNTEGIFRVSGSASKIEELKKKFDRGEDID--DLEDYDVHDVASLLKLYLRELPEPLIPFELYDE 78

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207147817 756 FISAIKMPDYKQKVQTVKDLMKKLPRPNHDTIQVLFKHLKKVIQHVDENRMTTQSVAIVFGPTLLRPEIETANMAVHMVY 835
Cdd:cd00159    79 FIELAKIEDEEERIEALKELLKSLPPENRDLLKYLLKLLHKISQNSEVNKMTASNLAIVFAPTLLRPPDSDDELLEDIKK 158

                  ....*....
gi 1207147817 836 QNQIVELIL 844
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 1207147817 659 VFGCSLSSlCQ--RENSTVPRFVWLCIEQVEKNGLGVDGLYRVSGNLAIIQKLRFAVNHE-EKIDLGDSKWEDIHVTTGA 735
Cdd:cd04395     1 TFGVPLDD-CPpsSENPYVPLIVEVCCNIVEARGLETVGIYRVPGNNAAISALQEELNRGgFDIDLQDPRWRDVNVVSSL 79

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207147817 736 LKMFFRELPEPLFTYTFFSDFISAIKMPDYKQKVQTVKDLMKKLPRPNHDTIQVLFKHLKKVIQHVDENRMTTQSVAIVF 815
Cdd:cd04395    80 LKSFFRKLPEPLFTNELYPDFIEANRIEDPVERLKELRRLIHSLPDHHYETLKHLIRHLKTVADNSEVNKMEPRNLAIVF 159

                         170       180       190
                  ....*....|....*....|....*....|....*..
gi 1207147817 816 GPTLLRPEIET-ANMAVHMVYQNQIVELILMEYDTIF 851
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 1207147817 660 FGCSLSSLCQRENSTVPRFVWLCIEQVEKNGLGVDGLYRVSGNLAIIQKLRFAVNHE-EKIDLGDSKWEDIHVTTGALKM 738
Cdd:cd04372     1 YGCDLTTLVKAHNTQRPMVVDMCIREIEARGLQSEGLYRVSGFAEEIEDVKMAFDRDgEKADISATVYPDINVITGALKL 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207147817 739 FFRELPEPLFTYTFFSDFISAIKMPDYKQKVQTVKDLMKKLPRPNHDTIQVLFKHLKKVIQHVDENRMTTQSVAIVFGPT 818
Cdd:cd04372    81 YFRDLPIPVITYDTYPKFIDAAKISNPDERLEAVHEALMLLPPAHYETLRYLMEHLKRVTLHEKDNKMNAENLGIVFGPT 160

                         170       180       190
                  ....*....|....*....|....*....|....
gi 1207147817 819 LLRPEIETANMAVH-MVYQNQIVELILMEYDTIF 851
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 1207147817 660 FGCSLSSLCQrENSTVPRFVWLCIEQVEKNGLGVDGLYRVSGNLAIIQKLRFAVNHE-EKIDLGDSKwedIHVTTGALKM 738
Cdd:cd04377     1 FGVSLSSLTS-EDRSVPLVLEKLLEHIEMHGLYTEGIYRKSGSANKIKELRQGLDTDpDSVNLEDYP---IHVITSVLKQ 76

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207147817 739 FFRELPEPLFTYTFFSDFISAIKMPDYKQKVQTVKDLMKKLPRPNHDTIQVLFKHLKKVIQHVDENRMTTQSVAIVFGPT 818
Cdd:cd04377    77 WLRELPEPLMTFELYENFLRAMELEEKQERVRALYSVLEQLPRANLNTLERLIFHLVRVALQEEVNRMSANALAIVFAPC 156

                         170       180       190
                  ....*....|....*....|....*....|
gi 1207147817 819 LLR-PEIETANMAVHMVY-QNQIVELILME 846
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 1207147817 470 EKCATLNMTKITEHGKKVRKNWTSYWTVLQGSLLIFNKgqgggsgwfgrDQKSSV---------EYSVDLKGGSVDWAsK 540
Cdd:cd13233     1 EKQGLLNKTKIAENGKKLRKNWSTSWVVLTSSHLLFYK-----------DAKSAAksgnpyskpESSVDLRGASIEWA-K 68

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|
gi 1207147817 541 DKSSKKHVLELKTRQGTELLLQSDSDGLVNDWHKALTEAI 580
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 1207147817 660 FGCSLSSLCQRENSTVPRFVWLCIEQVEKNGLGVDGLYRVSGNLAIIQKLRFAVNHEEKIDLGDSKWEDIHVTTGALKMF 739
Cdd:cd04387     1 FGVKISTVTKRERSKVPYIVRQCVEEVERRGMEEVGIYRISGVATDIQALKAAFDTNNKDVSVMLSEMDVNAIAGTLKLY 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207147817 740 FRELPEPLFTYTFFSDFISAIKMPDYKQKVQTVKDLMKKLPRPNHDTIQVLFKHLKKVIQHVDENRMTTQSVAIVFGPTL 819
Cdd:cd04387    81 FRELPEPLFTDELYPNFAEGIALSDPVAKESCMLNLLLSLPDPNLVTFLFLLHHLKRVAEREEVNKMSLHNLATVFGPTL 160

                         170       180
                  ....*....|....*....|...
gi 1207147817 820 LRPEIETANMAVHMVYQNQIVEL 842
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 1207147817 658 QVFGCSLSSLCQR--ENSTVPRFVWLCIEQVEKNGLGVDGLYRVSGNLAIIQKLRFAVNHEEKIDLGDskWEDIHVTTGA 735
Cdd:cd04404     4 QQFGVSLQFLKEKnpEQEPIPPVVRETVEYLQAHALTTEGIFRRSANTQVVKEVQQKYNMGEPVDFDQ--YEDVHLPAVI 81

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207147817 736 LKMFFRELPEPLFTYTFFSDfISAIKMPDYKQKVQTVKDLMKKLPRPNHDTIQVLFKHLKKVIQHVDENRMTTQSVAIVF 815
Cdd:cd04404    82 LKTFLRELPEPLLTFDLYDD-IVGFLNVDKEERVERVKQLLQTLPEENYQVLKYLIKFLVQVSAHSDQNKMTNSNLAVVF 160

                         170       180       190
                  ....*....|....*....|....*....|....*.
gi 1207147817 816 GPTLLRPEIETANMAVhMVYQNQIVELILMEYDTIF 851
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 1207147817  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 1207147817  67 EVRRALMPPPKPLniagrgGPAPNRPSALEI---QRPNDN-----------KKSPCPSPSS----TALLPPRDDRGSPVS 128
Cdd:pfam16618   1 EVRKALMPPPKPI------AHPNSPPKVLDIgplQRSTENlnkppelssfgRPSPSQTTSPsshfTPPALRRDANQNLGS 74

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207147817 129 PTRHLPPA------------QMNTFPGSLPCFRAESP-GSKLDGERDKDKDSERkdrgekaavQEELAEEGgdSDKNRID 195
Cdd:pfam16618  75 PTDHEQSLaelllltnnngkFHHGSHSTLPRSRARSPsLGKFPGPEFLDVDKTE---------QCDSAGEG--SEKLRND 143

                         170       180       190
                  ....*....|....*....|....*....|....*....
gi 1207147817 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 1207147817 675 VPRFVWLCIEQVEKNGLGVDGLYRVSGNLAIIQKLRFAVNHEEKI-DLGDSkweDIHVTTGALKMFFRELPEPLFTYTFF 753
Cdd:cd04382    17 IPALIVHCVNEIEARGLTEEGLYRVSGSEREVKALKEKFLRGKTVpNLSKV---DIHVICGCLKDFLRSLKEPLITFALW 93

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207147817 754 SDFISAIKMPDYKQKVQTVKDLMKKLPRPNHDTIQVLFKHLKKVIQhVDENRMTTQSVAIVFGPTL---LRPEIETANMA 830
Cdd:cd04382    94 KEFMEAAEILDEDNSRAALYQAISELPQPNRDTLAFLILHLQRVAQ-SPECKMDINNLARVFGPTIvgySVPNPDPMTIL 172

                         170
                  ....*....|....
gi 1207147817 831 VHMVYQNQIVELIL 844
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 1207147817 659 VFGCSLSSLCQR-----ENSTVPRFVWLCIEQVEKNGLGVDGLYRVSGNLAIIQKLRFAVnhEEKIDLGDSKWEDIHV-- 731
Cdd:cd04391     1 LFGVPLSTLLERdqkkvPGSKVPLIFQKLINKLEERGLETEGILRIPGSAQRVKFLCQEL--EAKFYEGTFLWDQVKQhd 78

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207147817 732 TTGALKMFFRELPEPLFTYTFFSDFISAIKMPDYKQKVQTVKDLMKKLPRPNHDTIQVLFKHLKKVIQHVDENRMTTQSV 811
Cdd:cd04391    79 AASLLKLFIRELPQPLLTVEYLPAFYSVQGLPSKKDQLQALNLLVLLLPEANRDTLKALLEFLQKVVDHEEKNKMNLWNV 158

                         170
                  ....*....|.
gi 1207147817 812 AIVFGPTLLRP 822
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 1207147817 675 VPRFVWLCIEQVEKNGLGVDGLYRVSGNLAIIQKLRFAVNHEE---KIDLGDskwEDIHVTTGALKMFFRELPEPLFTYT 751
Cdd:cd04385    15 IPVIVDKCIDFITQHGLMSEGIYRKNGKNSSVKKLLEAFRKDArsvQLREGE---YTVHDVADVLKRFLRDLPDPLLTSE 91

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207147817 752 FFSDFISAIKMPDYKQKVQTVKDLMKKLPRPNHDTIQVLFKHLKKVIQHVDENRMTTQSVAIVFGPTLLRPEIETANMAV 831
Cdd:cd04385    92 LHAEWIEAAELENKDERIARYKELIRRLPPINRATLKVLIGHLYRVQKHSDENQMSVHNLALVFGPTLFQTDEHSVGQTS 171

                         170
                  ....*....|....*.
gi 1207147817 832 HMVyqnQIVELILMEY 847
Cdd:cd04385   172 HEV---KVIEDLIDNY 184