Centaurin gamma (CENTG) GTPase; The centaurins (alpha, beta, gamma, and delta) are large, multi-domain proteins that all contain an ArfGAP domain and ankyrin repeats, and in some cases, numerous additional domains. Centaurin gamma contains an additional GTPase domain near its N-terminus. The specific function of this GTPase domain has not been well characterized, but centaurin gamma 2 (CENTG2) may play a role in the development of autism. Centaurin gamma 1 is also called PIKE (phosphatidyl inositol (PI) 3-kinase enhancer) and centaurin gamma 2 is also known as AGAP (ArfGAP protein with a GTPase-like domain, ankyrin repeats and a Pleckstrin homology domain) or GGAP. Three isoforms of PIKE have been identified. PIKE-S (short) and PIKE-L (long) are brain-specific isoforms, with PIKE-S restricted to the nucleus and PIKE-L found in multiple cellular compartments. A third isoform, PIKE-A was identified in human glioblastoma brain cancers and has been found in various tissues. GGAP has been shown to have high GTPase activity due to a direct intramolecular interaction between the N-terminal GTPase domain and the C-terminal ArfGAP domain. In human tissue, AGAP mRNA was detected in skeletal muscle, kidney, placenta, brain, heart, colon, and lung. Reduced expression levels were also observed in the spleen, liver, and small intestine.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 301604812  72 LKVGIVGNLASGKSALVHRYLTGTYVQEESPEGGRFKKEIVVDGQSYLLLIRDEGGPPEAQFAMWVDAVIFVFSLEDEIS 151
Cdd:cd04103    1 LKLGIVGNLRSGKSALVHRYLTGSYVQLESPEGGRFKKEVLVDGQSHLLLIRDEGGAPDAQFAGWVDAVIFVFSLEDEAS 80

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 301604812 152 FQTVYHYYSRLANYRNTSEIPMVLVGTQDAISCSNPRVIDDSRARKLSNDLKRCTYYETCATYGLNVERVFQDVAQKI 229
Cdd:cd04103   81 FQTVYRLYHQLSSYRNISEIPLILVGTQDAISASNPRVIDDARARQLCADMKRCSYYETCATYGLNVERVFQEAAQKI 158

Arf-GAP with GTPase, ANK repeat and PH domain-containing protein Pleckstrin homology (PH) domain; AGAP (also called centaurin gamma; PIKE/Phosphatidylinositol-3-kinase enhancer) reside mainly in the nucleus and are known to activate phosphoinositide 3-kinase, a key regulator of cell proliferation, motility and vesicular trafficking. There are 3 isoforms of AGAP (PIKE-A, PIKE-L, and PIKE-S) the longest of which PIKE-L consists of N-terminal proline rich domains (PRDs), followed by a GTPase domain, a split PH domain (PHN and PHC), an ArfGAP domain and two ankyrin repeats. PIKE-S terminates after the PHN domain and PIKE-A is missing the PRD region. Centaurin binds phosphatidlyinositol (3,4,5)P3. 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 301604812 344 RAIPIKQGMLLKRSGKSLNKEWKKKYVTLCDNGVLTYHPSLHDYMQNVHGKEIDLLRTTVKVPGKRPPRATSSCApvasp 423
Cdd:cd01250    1 RAIPIKQGYLYKRSSKSLNKEWKKKYVTLCDDGRLTYHPSLHDYMENVHGKEIDLLRTTVKVPGKRPPRASSKSA----- 75

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 301604812 424 ktngltkevsglqispntgnvtsstsvtqmasgpsgislgsfsrmdgmhqrsysvssadqwsegaviansaissdtglgd 503
Cdd:cd01250      --------------------------------------------------------------------------------

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 301604812 504 svcsspsissttspkldpppsphanrkkhrrkkstsnfkadglsstaeeqeenFEFIIVSLTSQSWHFEATSYEERDAWV 583
Cdd:cd01250   76 -----------------------------------------------------FEFIIVSLDGKQWHFEAASSEERDEWV 102

                        250
                 ....*....|..
gi 301604812 584 QAIESQILASLQ 595
Cdd:cd01250  103 QAIEQQILASLQ 114

Centaurin gamma (CENTG) GTPase; The centaurins (alpha, beta, gamma, and delta) are large, multi-domain proteins that all contain an ArfGAP domain and ankyrin repeats, and in some cases, numerous additional domains. Centaurin gamma contains an additional GTPase domain near its N-terminus. The specific function of this GTPase domain has not been well characterized, but centaurin gamma 2 (CENTG2) may play a role in the development of autism. Centaurin gamma 1 is also called PIKE (phosphatidyl inositol (PI) 3-kinase enhancer) and centaurin gamma 2 is also known as AGAP (ArfGAP protein with a GTPase-like domain, ankyrin repeats and a Pleckstrin homology domain) or GGAP. Three isoforms of PIKE have been identified. PIKE-S (short) and PIKE-L (long) are brain-specific isoforms, with PIKE-S restricted to the nucleus and PIKE-L found in multiple cellular compartments. A third isoform, PIKE-A was identified in human glioblastoma brain cancers and has been found in various tissues. GGAP has been shown to have high GTPase activity due to a direct intramolecular interaction between the N-terminal GTPase domain and the C-terminal ArfGAP domain. In human tissue, AGAP mRNA was detected in skeletal muscle, kidney, placenta, brain, heart, colon, and lung. Reduced expression levels were also observed in the spleen, liver, and small intestine.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 301604812  72 LKVGIVGNLASGKSALVHRYLTGTYVQEESPEGGRFKKEIVVDGQSYLLLIRDEGGPPEAQFAMWVDAVIFVFSLEDEIS 151
Cdd:cd04103    1 LKLGIVGNLRSGKSALVHRYLTGSYVQLESPEGGRFKKEVLVDGQSHLLLIRDEGGAPDAQFAGWVDAVIFVFSLEDEAS 80

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 301604812 152 FQTVYHYYSRLANYRNTSEIPMVLVGTQDAISCSNPRVIDDSRARKLSNDLKRCTYYETCATYGLNVERVFQDVAQKI 229
Cdd:cd04103   81 FQTVYRLYHQLSSYRNISEIPLILVGTQDAISASNPRVIDDARARQLCADMKRCSYYETCATYGLNVERVFQEAAQKI 158

Arf-GAP with GTPase, ANK repeat and PH domain-containing protein Pleckstrin homology (PH) domain; AGAP (also called centaurin gamma; PIKE/Phosphatidylinositol-3-kinase enhancer) reside mainly in the nucleus and are known to activate phosphoinositide 3-kinase, a key regulator of cell proliferation, motility and vesicular trafficking. There are 3 isoforms of AGAP (PIKE-A, PIKE-L, and PIKE-S) the longest of which PIKE-L consists of N-terminal proline rich domains (PRDs), followed by a GTPase domain, a split PH domain (PHN and PHC), an ArfGAP domain and two ankyrin repeats. PIKE-S terminates after the PHN domain and PIKE-A is missing the PRD region. Centaurin binds phosphatidlyinositol (3,4,5)P3. 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 301604812 344 RAIPIKQGMLLKRSGKSLNKEWKKKYVTLCDNGVLTYHPSLHDYMQNVHGKEIDLLRTTVKVPGKRPPRATSSCApvasp 423
Cdd:cd01250    1 RAIPIKQGYLYKRSSKSLNKEWKKKYVTLCDDGRLTYHPSLHDYMENVHGKEIDLLRTTVKVPGKRPPRASSKSA----- 75

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 301604812 424 ktngltkevsglqispntgnvtsstsvtqmasgpsgislgsfsrmdgmhqrsysvssadqwsegaviansaissdtglgd 503
Cdd:cd01250      --------------------------------------------------------------------------------

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 301604812 504 svcsspsissttspkldpppsphanrkkhrrkkstsnfkadglsstaeeqeenFEFIIVSLTSQSWHFEATSYEERDAWV 583
Cdd:cd01250   76 -----------------------------------------------------FEFIIVSLDGKQWHFEAASSEERDEWV 102

                        250
                 ....*....|..
gi 301604812 584 QAIESQILASLQ 595
Cdd:cd01250  103 QAIEQQILASLQ 114

Putative GTP-ase activating proteins for the small GTPase, ARF; Putative zinc fingers with GTPase activating proteins (GAPs) towards the small GTPase, Arf. The GAP of ARD1 stimulates GTPase hydrolysis for ARD1 but not ARFs.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 301604812   615 LQSIRNLPGNSHCVDCDAQNPDWASLNLGALMCIECSGIHRNLGTHLSRVRSLDLDDWPPELIKVMSAIGNELANSVWEG 694
Cdd:smart00105   1 LKLLRSIPGNKKCFDCGAPNPTWASVNLGVFLCIECSGIHRSLGVHISKVRSLTLDTWTEEELRLLQKGGNENANSIWES 80

                           90       100       110
                   ....*....|....*....|....*....|....*....
gi 301604812   695 S-SQGHVKPCSESPREEKERWIRAKYEQKLFLSPLPCRD 732
Cdd:smart00105  81 NlDDFSLKPPDDDDQQKYESFIAAKYEEKLFVPPESAEE 119

Ras subfamily of RAS small GTPases; Similar in fold and function to the bacterial EF-Tu GTPase. p21Ras couples receptor Tyr kinases and G protein receptors to protein kinase cascades

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 301604812    73 KVGIVGNLASGKSALVHRYLTGTYVQEESP--EGGrFKKEIVVDGQSYLLLIRDEGGppEAQF-AM---WV---DAVIFV 143
Cdd:smart00173   2 KLVVLGSGGVGKSALTIQFIQGHFVDDYDPtiEDS-YRKQIEIDGEVCLLDILDTAG--QEEFsAMrdqYMrtgEGFLLV 78

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 301604812   144 FSLEDEISFQTVYHYYSRLANYRNTSEIPMVLVGTQdaisC--SNPRVIDDSRARKLSNDLKrCTYYETCATYGLNVERV 221
Cdd:smart00173  79 YSITDRQSFEEIKKFREQILRVKDRDDVPIVLVGNK----CdlESERVVSTEEGKELARQWG-CPFLETSAKERVNVDEA 153

                          170
                   ....*....|....
gi 301604812   222 FQDVAQKIvatRKK 235
Cdd:smart00173 154 FYDLVREI---RKK 164

ADP-ribosylation factor GTPase-activating protein AGD10; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 301604812 624 NSHCVDCDAQNPDWASLNLGALMCIECSGIHRNLGTHLSRVRSLDLDDWPPELIKVMSAIGNELANSV-----WEGSSQG 698
Cdd:PLN03114  22 NKICFDCNAKNPTWASVTYGIFLCIDCSAVHRSLGVHISFVRSTNLDSWSSEQLKMMIYGGNNRAQVFfkqygWSDGGKT 101

                         90       100       110
                 ....*....|....*....|....*....|....*
gi 301604812 699 HVKPCSESPREEKE----RWIRAKYEQKLFLSPLP 729
Cdd:PLN03114 102 EAKYTSRAADLYKQilakEVAKSKAEEELDLPPSP 136

GTPase SAR1 family domain [General function prediction only];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 301604812  71 ELKVGIVGNLASGKSALVHRYLTGTYVQEE--SPEG-GRFKKEIVVDGQSYLLLIRDEGGPPE-----AQFAMWV---DA 139
Cdd:COG1100    3 EKKIVVVGTGGVGKTSLVNRLVGDIFSLEKylSTNGvTIDKKELKLDGLDVDLVIWDTPGQDEfretrQFYARQLtgaSL 82

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 301604812 140 VIFVFSLEDEISFQTVYHYYSRLANYRNTSeiPMVLVGTQ-DAIscSNPRVIDDSRARKLSNDLKRCTYYETCATYGLNV 218
Cdd:COG1100   83 YLFVVDGTREETLQSLYELLESLRRLGKKS--PIILVLNKiDLY--DEEEIEDEERLKEALSEDNIVEVVATSAKTGEGV 158

                        170
                 ....*....|.
gi 301604812 219 ERVFQDVAQKI 229
Cdd:COG1100  159 EELFAALAEIL 169

Ras-like protein; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 301604812  71 ELKVGIVGNLASGKSALVHRYLTGTYVQEESPE-GGRFKKEIVVDGQSYLLLIRDEGGPPE-----AQFAMWVDAVIFVF 144
Cdd:PTZ00369   5 EYKLVVVGGGGVGKSALTIQFIQNHFIDEYDPTiEDSYRKQCVIDEETCLLDILDTAGQEEysamrDQYMRTGQGFLCVY 84

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 301604812 145 SLEDEISFQTVYHYYSRLANYRNTSEIPMVLVGTQDAIscSNPRVIDDSRARKLSNDLKrCTYYETCATYGLNVERVFQD 224
Cdd:PTZ00369  85 SITSRSSFEEIASFREQILRVKDKDRVPMILVGNKCDL--DSERQVSTGEGQELAKSFG-IPFLETSAKQRVNVDEAFYE 161

                 ....*
gi 301604812 225 VAQKI 229
Cdd:PTZ00369 162 LVREI 166

Pleckstrin homology domain; Domain commonly found in eukaryotic signalling proteins. The domain family possesses multiple functions including the abilities to bind inositol phosphates, and various proteins. PH domains have been found to possess inserted domains (such as in PLC gamma, syntrophins) and to be inserted within other domains. Mutations in Brutons tyrosine kinase (Btk) within its PH domain cause X-linked agammaglobulinaemia (XLA) in patients. Point mutations cluster into the positively charged end of the molecule around the predicted binding site for phosphatidylinositol lipids.

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 301604812   347 PIKQGMLLKRSGKSlNKEWKKKYVTLCdNGVLTYHPSLHDYMQNVHGKEIDLLRTTVKVPGKRPP 411
Cdd:smart00233   1 VIKEGWLYKKSGGG-KKSWKKRYFVLF-NSTLLYYKSKKDKKSYKPKGSIDLSGCTVREAPDPDS 63

Centaurin gamma (CENTG) GTPase; The centaurins (alpha, beta, gamma, and delta) are large, multi-domain proteins that all contain an ArfGAP domain and ankyrin repeats, and in some cases, numerous additional domains. Centaurin gamma contains an additional GTPase domain near its N-terminus. The specific function of this GTPase domain has not been well characterized, but centaurin gamma 2 (CENTG2) may play a role in the development of autism. Centaurin gamma 1 is also called PIKE (phosphatidyl inositol (PI) 3-kinase enhancer) and centaurin gamma 2 is also known as AGAP (ArfGAP protein with a GTPase-like domain, ankyrin repeats and a Pleckstrin homology domain) or GGAP. Three isoforms of PIKE have been identified. PIKE-S (short) and PIKE-L (long) are brain-specific isoforms, with PIKE-S restricted to the nucleus and PIKE-L found in multiple cellular compartments. A third isoform, PIKE-A was identified in human glioblastoma brain cancers and has been found in various tissues. GGAP has been shown to have high GTPase activity due to a direct intramolecular interaction between the N-terminal GTPase domain and the C-terminal ArfGAP domain. In human tissue, AGAP mRNA was detected in skeletal muscle, kidney, placenta, brain, heart, colon, and lung. Reduced expression levels were also observed in the spleen, liver, and small intestine.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 301604812  72 LKVGIVGNLASGKSALVHRYLTGTYVQEESPEGGRFKKEIVVDGQSYLLLIRDEGGPPEAQFAMWVDAVIFVFSLEDEIS 151
Cdd:cd04103    1 LKLGIVGNLRSGKSALVHRYLTGSYVQLESPEGGRFKKEVLVDGQSHLLLIRDEGGAPDAQFAGWVDAVIFVFSLEDEAS 80

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 301604812 152 FQTVYHYYSRLANYRNTSEIPMVLVGTQDAISCSNPRVIDDSRARKLSNDLKRCTYYETCATYGLNVERVFQDVAQKI 229
Cdd:cd04103   81 FQTVYRLYHQLSSYRNISEIPLILVGTQDAISASNPRVIDDARARQLCADMKRCSYYETCATYGLNVERVFQEAAQKI 158

ArfGAP with GTPase domain, ANK repeat and PH domain 2; The AGAP subfamily of ADP-ribosylation factor GTPase-activating proteins (Arf GAPs) includes three members: AGAP1-3. In addition to the Arf GAP domain, AGAP proteins contain GTP-binding protein-like, ANK repeat and pleckstrin homology (PH) domains. AGAP1 and AGAP2 have phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2)-mediated GTPase-activating protein (GAP) activity preferentially toward Arf1, and function in the endocytic system. AGAP1 and AGAP2 independently regulate AP-3 endosomes and AP-1/Rab4 fast recycling endosomes, respectively. AGAP1, via its PH domain, directly interacts with the adapter protein 3 (AP-3), which is a coat protein involved in trafficking in the endosomal-lysosomal system, and regulates AP-3-dependent trafficking. In other hand, AGAP2 specifically binds the clathrin adaptor protein AP-1 and regulates the AP-1/Rab-4 dependent endosomal trafficking. AGAP2 is overexpressed in different human cancers including prostate carcinoma and glioblastoma, and promotes cancer cell invasion. AGAP3 exists as a component of the NMDA receptor complex that regulates Arf6 and Ras/ERK signaling pathways. Moreover, AGAP3 regulates AMPA receptor trafficking through the ArfGAP domain. Together, AGAP3 is believed to involve in linking NMDA receptor activation to AMPA receptor trafficking.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 301604812 612 ALALQSIRNLPGNSHCVDCDAQNPDWASLNLGALMCIECSGIHRNLGTHLSRVRSLDLDDWPPELIKVMSAIGNELANSV 691
Cdd:cd08853    1 AMALQSIRNMRGNSHCVDCETQNPKWASLNLGVLMCIECSGIHRNLGTHLSRVRSLDLDDWPVELRKVMSSIGNELANSI 80

                         90       100
                 ....*....|....*....|....*....
gi 301604812 692 WEGSSQGHVKPCSESPREEKERWIRAKYE 720
Cdd:cd08853   81 WEGSSQGQTKPSSDSTREEKERWIRAKYE 109

ArfGAP with GTPase domain, ANK repeat and PH domain 1; The AGAP subfamily of ADP-ribosylation factor GTPase-activating proteins (Arf GAPs) includes three members: AGAP1-3. In addition to the Arf GAP domain, AGAP proteins contain GTP-binding protein-like, ANK repeat and pleckstrin homology (PH) domains. AGAP1 and AGAP2 have phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2)-mediated GTPase-activating protein (GAP) activity preferentially toward Arf1, and function in the endocytic system. AGAP1 and AGAP2 independently regulate AP-3 endosomes and AP-1/Rab4 fast recycling endosomes, respectively. AGAP1, via its PH domain, directly interacts with the adapter protein 3 (AP-3), which is a coat protein involved in trafficking in the endosomal-lysosomal system, and regulates AP-3-dependent trafficking. In other hand, AGAP2 specifically binds the clathrin adaptor protein AP-1 and regulates the AP-1/Rab-4 dependent endosomal trafficking. AGAP2 is overexpressed in different human cancers including prostate carcinoma and glioblastoma, and promotes cancer cell invasion. AGAP3 exists as a component of the NMDA receptor complex that regulates Arf6 and Ras/ERK signaling pathways. Moreover, AGAP3 regulates AMPA receptor trafficking through the ArfGAP domain. Together, AGAP3 is believed to involve in linking NMDA receptor activation to AMPA receptor trafficking.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 301604812 612 ALALQSIRNLPGNSHCVDCDAQNPDWASLNLGALMCIECSGIHRNLGTHLSRVRSLDLDDWPPELIKVMSAIGNELANSV 691
Cdd:cd08854    1 AVAIQAIRNAKGNSLCVDCGAPNPTWASLNLGALICIECSGIHRNLGTHLSRVRSLDLDDWPRELTLVLTAIGNHMANSI 80

                         90       100
                 ....*....|....*....|....*....
gi 301604812 692 WEGSSQGHVKPCSESPREEKERWIRAKYE 720
Cdd:cd08854   81 WESCTQGRTKPAPDSSREERESWIRAKYE 109

GTPase-activating protein (GAP) for the ADP ribosylation factors (ARFs); ArfGAPs are a family of proteins containing an ArfGAP catalytic domain that induces the hydrolysis of GTP bound to the small guanine nucleotide-binding protein Arf, a member of the Ras superfamily of GTPases. Like all GTP-binding proteins, Arf proteins function as molecular switches, cycling between GTP (active-membrane bound) and GDP (inactive-cytosolic) form. Conversion to the GTP-bound form requires a guanine nucleotide exchange factor (GEF), whereas conversion to the GDP-bound form is catalyzed by a GTPase activating protein (GAP). In that sense, ArfGAPs were originally proposed to function as terminators of Arf signaling, which is mediated by regulating Arf family GTP-binding proteins. However, recent studies suggest that ArfGAPs can also function as Arf effectors, independently of their GAP enzymatic activity to transduce signals in cells. The ArfGAP domain contains a C4-type zinc finger motif and a conserved arginine that is required for activity, within a specific spacing (CX2CX16CX2CX4R). ArfGAPs, which have multiple functional domains, regulate the membrane trafficking and actin cytoskeleton remodeling via specific interactions with signaling lipids such as phosphoinositides and trafficking proteins, which consequently affect cellular events such as cell growth, migration, and cancer invasion. The ArfGAP family, which includes 31 human ArfGAP-domain containing proteins, is divided into 10 subfamilies based on domain structure and sequence similarity. The ArfGAP nomenclature is mainly based on the protein domain structure. For example, ASAP1 contains ArfGAP, SH3, ANK repeat and PH domains; ARAPs contain ArfGAP, Rho GAP, ANK repeat and PH domains; ACAPs contain ArfGAP, BAR (coiled coil), ANK repeat and PH domains; and AGAPs contain Arf GAP, GTP-binding protein-like, ANK repeat and PH domains. Furthermore, the ArfGAPs can be classified into two major types of subfamilies, according to the overall domain structure: the ArfGAP1 type includes 6 subfamilies (ArfGAP1, ArfGAP2/3, ADAP, SMAP, AGFG, and GIT), which contain the ArfGAP domain at the N-terminus of the protein; and the AZAP type includes 4 subfamilies (ASAP, ACAP, AGAP, and ARAP), which contain an ArfGAP domain between the PH and ANK repeat domains.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 301604812 615 LQSIRNLPGNSHCVDCDAQNPDWASLNLGALMCIECSGIHRNLGTHLSRVRSLDLDDWPPELIKVMSAIGNELANSVWEG 694
Cdd:cd08204    1 LEELLKLPGNKVCADCGAPDPRWASINLGVFICIRCSGIHRSLGVHISKVRSLTLDSWTPEQVELMKAIGNARANAYYEA 80

                         90       100
                 ....*....|....*....|....*.
gi 301604812 695 S-SQGHVKPCSESPREEKERWIRAKY 719
Cdd:cd08204   81 NlPPGFKKPTPDSSDEEREQFIRAKY 106

ArfGAP domain of ACAP (ArfGAP with Coiled-coil, ANK repeat and PH domains) proteins; ArfGAP domain is an essential part of ACAP proteins that play important role in endocytosis, actin remodeling and receptor tyrosine kinase-dependent cell movement. ACAP subfamily of ArfGAPs are composed of coiled coils (BAR, Bin-Amphiphysin-Rvs), PH, ArfGAP and ANK repeats domains. ACAP1 (centaurin beta1) and ACAP2 centaurin beta2) have a GAP (GTPase-activating protein) activity preferentially toward Arf6, which regulates endocytic recycling. Both ACAP1/2 are activated by are activated by the phosphoinositides, PI(4,5)P2 and PI(3,5)P2. ACAP1 binds specifically with recycling cargo proteins such as transferrin receptor (TfR) and cellubrevin. Thus, ACAP1 promotes cargo sorting to enhance TfR recycling from the recycling endosome. In addition, phosphorylation of ACAP by Akt, a serine/threonine protein kinase, regulates the recycling of integrin beta1 to control cell migration. In contrast, ACAP2 does not exhibit a similar interaction with the recycling cargo proteins. It has been shown that ACAP2 functions both as an effector of Ras-related protein Rab35 and as an Arf6-GTPase-activating protein (GAP) during neurite outgrowth of PC12 cells. In addition, ACAP2, together with Rab35, regulates phagocytosis in mammalian macrophages. ACAP3 also positively regulates neurite outgrowth through its GAP activity specific to Arf6 in mouse hippocampal neurons.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 301604812 614 ALQSIRNLPGNSHCVDCDAQNPDWASLNLGALMCIECSGIHRNLGTHLSRVRSLDLDDWPPELIKVMSAIGNELANSVWE 693
Cdd:cd08835    3 ALEQVLSVPGNAQCCDCGSPDPRWASINLGVTLCIECSGIHRSLGVHVSKVRSLTLDSWEPELLKVMLELGNDVVNRIYE 82

                         90       100       110
                 ....*....|....*....|....*....|....
gi 301604812 694 GSSQ--GHVKPCSESPREEKERWIRAKYEQKLFL 725
Cdd:cd08835   83 ANVPddGSVKPTPDSSRQEREAWIRAKYVEKKFV 116

ArfGAP domain of ACAP3 (ArfGAP with Coiled-coil, ANK repeat and PH domains 3); ACAP3 belongs to the ACAP subfamily of GAPs (GTPase-activating proteins) for the small GTPase Arf (ADP-ribosylation factor). ACAP subfamily of ArfGAPs are composed of Coiled coli (BAR, Bin-Amphiphysin-Rvs), PH, ArfGAP and ANK repeats domains. It has been shown that ACAP3 positively regulates neurite outgrowth through its GAP activity specific to Arf6 in mouse hippocampal neurons. ACAP1 (centaurin beta1) and ACAP2 centaurin beta2) also have a GAP (GTPase-activating protein) activity preferentially toward Arf6, which regulates endocytic recycling. Both ACAP1/2 are activated by are activated by the phosphoinositides, PI(4,5)P2 and PI(3,5)P2. ACAP1 binds specifically with recycling cargo proteins such as transferrin receptor (TfR) and cellubrevin. Thus, ACAP1 promotes cargo sorting to enhance TfR recycling from the recycling endosome. In addition, phosphorylation of ACAP by Akt, a serine/threonine protein kinase, regulates the recycling of integrin beta1 to control cell migration. In contrast, ACAP2 does not exhibit a similar interaction with the recycling cargo proteins. It has been shown that ACAP2 functions both as an effector of Ras-related protein Rab35 and as an Arf6-GTPase-activating protein (GAP) during neurite outgrowth of PC12 cells. Moreover, ACAP2, together with Rab35, regulates phagocytosis in mammalian macrophages.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 301604812 615 LQSIRNLPGNSHCVDCDAQNPDWASLNLGALMCIECSGIHRNLGTHLSRVRSLDLDDWPPELIKVMSAIGNELANSVWEG 694
Cdd:cd08850    4 LQRVQSIAGNDQCCDCGQPDPRWASINLGILLCIECSGIHRSLGVHCSKVRSLTLDSWEPELLKLMCELGNSTVNQIYEA 83

                         90       100       110
                 ....*....|....*....|....*....|...
gi 301604812 695 SSQ--GHVKPCSESPREEKERWIRAKYEQKLFL 725
Cdd:cd08850   84 QCEelGLKKPTASSSRQDKEAWIKAKYVEKKFL 116

ArfGAP domain of ACAP2 (ArfGAP with Coiled-coil, ANK repeat and PH domains 2); ACAP2 belongs to the ACAP subfamily of GAPs (GTPase-activating proteins) for the small GTPase Arf (ADP-ribosylation factor). ACAP subfamily of ArfGAPs are composed of Coiled coli (BAR, Bin-Amphiphysin-Rvs), PH, ArfGAP and ANK repeats domains. ACAP1 (centaurin beta1) and ACAP2 centaurin beta2) have a GAP (GTPase-activating protein) activity preferentially toward Arf6, which regulates endocytic recycling. Both ACAP1/2 are activated by are activated by the phosphoinositides, PI(4,5)P2 and PI(3,5)P2. ACAP1 binds specifically with recycling cargo proteins such as transferrin receptor (TfR) and cellubrevin. Thus, ACAP1 promotes cargo sorting to enhance TfR recycling from the recycling endosome. In addition, phosphorylation of ACAP by Akt, a serine/threonine protein kinase, regulates the recycling of integrin beta1 to control cell migration. In contrast, ACAP2 does not exhibit a similar interaction with the recycling cargo proteins. It has been shown that ACAP2 functions both as an effector of Ras-related protein Rab35 and as an Arf6-GTPase-activating protein (GAP) during neurite outgrowth of PC12 cells. Moreover, ACAP2, together with Rab35, regulates phagocytosis in mammalian macrophages. ACAP3 also positively regulates neurite outgrowth through its GAP activity specific to Arf6 in mouse hippocampal neurons.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 301604812 614 ALQSIRNLPGNSHCVDCDAQNPDWASLNLGALMCIECSGIHRNLGTHLSRVRSLDLDDWPPELIKVMSAIGNELANSVWE 693
Cdd:cd08851    3 ALQRVQCIPGNASCCDCGLADPRWASINLGITLCIECSGIHRSLGVHFSKVRSLTLDTWEPELLKLMCELGNDVINRIYE 82

                         90       100       110
                 ....*....|....*....|....*....|....
gi 301604812 694 GSSQ--GHVKPCSESPREEKERWIRAKYEQKLFL 725
Cdd:cd08851   83 ARVEkmGAKKPQPGGQRQEKEAYIRAKYVERKFV 116

Stromal membrane-associated proteins; a subfamily of the ArfGAP family; The SMAP subfamily of Arf GTPase-activating proteins consists of the two structurally-related members, SMAP1 and SMAP2. Each SMAP member exhibits common and distinct functions in vesicle trafficking. They both bind to clathrin heavy chain molecules and are involved in the trafficking of clathrin-coated vesicles. SMAP1 preferentially exhibits GAP toward Arf6, while SMAP2 prefers Arf1 as a substrate. SMAP1 is involved in Arf6-dependent vesicle trafficking, but not Arf6-mediated actin cytoskeleton reorganization, and regulates clathrin-dependent endocytosis of the transferrin receptors and E-cadherin. SMAP2 regulates Arf1-dependent retrograde transport of TGN38/46 from the early endosome to the trans-Golgi network (TGN). SMAP2 has the Clathrin Assembly Lymphoid Myeloid (CALM)-binding domain, but SMAP1 does not.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 301604812 615 LQSIRNLPGNSHCVDCDAQNPDWASLNLGALMCIECSGIHRNLGTHLSRVRSLDLDDWPPELIKVMSAIGNELANSVWEG 694
Cdd:cd08839    1 LAKLLREEDNKYCADCGAKGPRWASWNLGVFICIRCAGIHRNLGVHISKVKSVNLDSWTPEQVQSMQEMGNARANAYYEA 80

                         90       100
                 ....*....|....*....|....*.
gi 301604812 695 S-SQGHVKPCSESpreEKERWIRAKY 719
Cdd:cd08839   81 NlPDGFRRPQTDS---ALENFIRDKY 103

Arf1 GTPase-activating protein 1; ArfGAP (ADP Ribosylation Factor GTPase Activating Protein) domain is a part of ArfGap1-like proteins that play a crucial role in controlling of membrane trafficking, particularly in the formation of COPI (coat protein complex I)-coated vesicles on Golgi membranes. The ArfGAP1 protein subfamily consists of three members: ArfGAP1 (Gcs1p in yeast), ArfGAP2 and ArfGAP3 (both are homologs of yeast Glo3p). ArfGAP2/3 are closely related, but with little similarity to ArfGAP1, except the catalytic ArfGAP domain. They promote hydrolysis of GTP bound to the small G protein ADP-ribosylation factor 1 (Arf1), which leads to the dissociation of coat proteins from Golgi-derived membranes and vesicles. Dissociation of the coat proteins is required for the fusion of these vesicles with target compartments. Thus, the GAP catalytic activity plays a key role in the formation of COPI vesicles from Golgi membrane. In contrast to ArfGAP1, which displays membrane curvature-dependent ArfGAP activity, ArfGAP2 and ArfGAP3 activities are dependent on coatomer (the core COPI complex) which required for efficient recruitment of ArfGAP2 and ArfGAP3 to the Golgi membrane. Accordingly, ArfGAP2/3 has been implicated in coatomer-mediated protein transport between the Golgi complex and the endoplasmic reticulum. Unlike ArfGAP1, which is controlled by membrane curvature through its amphipathic lipid packing sensor (ALPS) motifs, ArfGAP2/3 do not possess ALPS motif.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 301604812 615 LQSIRNLPGNSHCVDCDAQNPDWASLNLGALMCIECSGIHRNLGTHLSRVRSLDLDDWPPELIKVMSAIGNELANSVWEg 694
Cdd:cd08830    5 LRELQKLPGNNRCFDCGAPNPQWASVSYGIFICLECSGVHRGLGVHISFVRSITMDSWSEKQLKKMELGGNAKLREFFE- 83

                         90       100       110
                 ....*....|....*....|....*....|
gi 301604812 695 sSQGhvkPCSESPREEKER-WIRAKYEQKL 723
Cdd:cd08830   84 -SYG---ISPDLPIREKYNsKAAELYREKL 109

ArfGap with Rho-Gap domain, ANK repeat and PH domain-containing proteins; The ARAP subfamily includes three members, ARAP1-3, and belongs to the ADP-ribosylation factor GTPase-activating proteins (Arf GAPs) family of proteins that promotes the hydrolysis of GTP bound to Arf, thereby inactivating Arf signaling. The function of Arfs is dependent on GAPs and guanine nucleotide exchange factors (GEFs), which allow Arfs to cycle between the GDP-bound and GTP-bound forms. In addition to the Arf GAP domain, ARAPs contain the SAM (sterile-alpha motif) domain, 5 pleckstrin homology (PH) domains, the Rho-GAP domain, the Ras-association domain, and ANK repeats. ARAPs show phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3)-dependent GAP activity toward Arf6. ARAPs play important roles in endocytic trafficking, cytoskeleton reorganization in response to growth factors stimulation, and focal adhesion dynamics.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 301604812 615 LQSIRNLPGNSHCVDCDAQNPDWASLNLGALMCIECSGIHRNLGTHLSRVRSLDLDD--WPPELIKVMSAIGNELANSVW 692
Cdd:cd08837    4 AEKIWSNPANRFCADCGAPDPDWASINLCVVICKQCAGEHRSLGSNISKVRSLKMDTkvWTEELVELFLKLGNDRANRFW 83

                         90       100       110
                 ....*....|....*....|....*....|....*.
gi 301604812 693 EgssqGHVKP----CSESPREEKERWIRAKYEQKLF 724
Cdd:cd08837   84 A----ANLPPsealHPDADSEQRREFITAKYREGKY 115

ARF1 GTPase-activating protein 1-like; ArfGAP (ADP Ribosylation Factor GTPase Activating Protein) domain is a part of ArfGap1-like proteins that play a crucial role in controlling of membrane trafficking, particularly in the formation of COPI (coat protein complex I)-coated vesicles on Golgi membranes. The ArfGAP1 protein subfamily consists of three members: ArfGAP1 (Gcs1p in yeast), ArfGAP2 and ArfGAP3 (both are homologs of yeast Glo3p). ArfGAP2/3 are closely related, but with little similarity to ArfGAP1, except the catalytic ArfGAP domain. They promote hydrolysis of GTP bound to the small G protein ADP-ribosylation factor 1 (Arf1), which leads to the dissociation of coat proteins from Golgi-derived membranes and vesicles. Dissociation of the coat proteins is required for the fusion of these vesicles with target compartments. Thus, the GAP catalytic activity plays a key role in the formation of COPI vesicles from Golgi membrane. In contrast to ArfGAP1, which displays membrane curvature-dependent ArfGAP activity, ArfGAP2 and ArfGAP3 activities are dependent on coatomer (the core COPI complex) which required for efficient recruitment of ArfGAP2 and ArfGAP3 to the Golgi membrane. Accordingly, ArfGAP2/3 has been implicated in coatomer-mediated protein transport between the Golgi complex and the endoplasmic reticulum. Unlike ArfGAP1, which is controlled by membrane curvature through its amphipathic lipid packing sensor (ALPS) motifs, ArfGAP2/3 do not possess ALPS motif.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 301604812 615 LQSIRNLPGNSHCVDCDAQNPDWASLNLGALMCIECSGIHRNLGTHLSRVRSLDLDDWPPELIKVMSAIGNELANSVWEg 694
Cdd:cd08959    5 FKKLRSKPENKVCFDCGAKNPQWASVTYGIFICLDCSGVHRGLGVHISFVRSTTMDKWTEEQLRKMKVGGNANAREFFK- 83

                         90       100
                 ....*....|....*....|....*....
gi 301604812 695 sSQGHVKpcSESPREEKERWIRAKYEQKL 723
Cdd:cd08959   84 -QHGIYD--SMDIKEKYNSRAAALYRDKL 109

ArfGAP domain of ASAP3 (ArfGAP with ANK repeat and PH domain-containing protein 3); The ArfGAPs are a family of multidomain proteins with a common catalytic domain that promotes the hydrolysis of GTP bound to Arf, thereby inactivating Arf signaling. ASAP-subfamily GAPs include three members: ASAP1, ASAP2, ASAP3. The ASAP subfamily comprises Arf GAP, SH3, ANK repeat and PH domains. From the N-terminus, each member has a BAR, PH, Arf GAP, ANK repeat, and proline rich domains. Unlike ASAP1 and ASAP2, ASAP3 do not have an SH3 domain at the C-terminus. ASAP1 and ASAP2 show strong GTPase-activating protein (GAP) activity toward Arf1 and Arf5 and weak activity toward Arf6. ASAP1 is a target of Src and FAK signaling that regulates focal adhesions, circular dorsal ruffles (CDR), invadopodia, and podosomes. ASAP1 GAP activity is synergistically stimulated by phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidic acid. ASAP2 is believed to function as an ArfGAP that controls ARF-mediated vesicle budding when recruited to Golgi membranes. It also functions as a substrate and downstream target for protein tyrosine kinases Pyk2 and Src, a pathway that may be involved in the regulation of vesicular transport. ASAP3 is a focal adhesion-associated ArfGAP that functions in cell migration and invasion. Similar to ASAP1, the GAP activity of ASAP3 is strongly enhanced by PIP2 via PH domain. Like ASAP1, ASAP3 associates with focal adhesions and circular dorsal ruffles. However, unlike ASAP1, ASAP3 does not localize to invadopodia or podosomes. ASAP 1 and 3 have been implicated in oncogenesis, as ASAP1 is highly expressed in metastatic breast cancer and ASAP3 in hepatocellular carcinoma.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 301604812 613 LALQSIRNLPGNSHCVDCDAQNPDWASLNLGALMCIECSGIHRNLGTHLSRVRSLDLDDWPPELIKVMSAIGNELANSVW 692
Cdd:cd17900    4 LLIAEVKSRPGNSQCCDCGAPDPTWLSTNLGILTCIECSGIHRELGVRYSRIQSLTLDLLSTSELLLAVSMGNTRFNEVM 83

                         90       100       110
                 ....*....|....*....|....*....|....*.
gi 301604812 693 EGS--SQGHVKPCSESPREEKERWIRAKYEQKLFLS 726
Cdd:cd17900   84 EATlpAHGGPKPSAESDMGTRKDYIMAKYVEHRFVR 119

ArfGap with Rho-Gap domain, ANK repeat and PH domain-containing protein 1; The ARAP subfamily includes three members, ARAP1-3, and belongs to the ADP-ribosylation factor GTPase-activating proteins (Arf GAPs) family of proteins that promotes the hydrolysis of GTP bound to Arf, thereby inactivating Arf signaling. The function of Arfs is dependent on GAPs and guanine nucleotide exchange factors (GEFs), which allow Arfs to cycle between the GDP-bound and GTP-bound forms. In addition to the Arf GAP domain, ARAPs contain the SAM (sterile-alpha motif) domain, 5 pleckstrin homology (PH) domains, the Rho-GAP domain, the Ras-association domain, and ANK repeats. ARAPs show phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3)-dependent GAP activity toward Arf6. ARAPs play important roles in endocytic trafficking, cytoskeleton reorganization in response to growth factors stimulation, and focal adhesion dynamics. ARAP1 localizes to the plasma membrane, the Golgi complex, and endosomal compartments. It displays PI(3,4,5)P3-dependent ArfGAP activity that regulates Arf-, RhoA-, and Cdc42-dependent cellular events. For example, ARAP1 inhibits the trafficking of epidermal growth factor receptor (EGFR) to the early endosome.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 301604812 616 QSIRNLPGNSHCVDCDAQNPDWASLNLGALMCIECSGIHRNLGTHLSRVRSLDLDD--WPPELIKVMSAIGNELANSVWE 693
Cdd:cd17901    5 EKIWSVESNRFCADCGSPKPDWASVNLCVVICKRCAGEHRGLGPSVSKVRSLKMDRkvWTEELIELFLLLGNGKANQFWA 84

                         90       100
                 ....*....|....*....|....*...
gi 301604812 694 GSSQGHVKPCSESPREEKERWIRAKYEQ 721
Cdd:cd17901   85 ANVPPSEALCPSSSSEERRHFITAKYKE 112

ADAP2 GTPase activating protein for Arf, with dual PH domains; The ADAP subfamily, ArfGAPs with dual pleckstrin homology (PH) domains, includes two members: ADAP1 and ADAP2. Both ADAP1 (also known as centaurin-alpha1, p42(IP4), or PIP3BP) and ADAP2 (centaurin-alpha2) display a GTPase-activating protein (GAP) activity toward Arf6 (ADP-ribosylation factor 6), which is involved in protein trafficking that regulates endocytic recycling, cytoskeleton remodeling, and neuronal differentiation. ADAP2 has high sequence similarity to the ADAP1 and they both contain a ArfGAP domain at the N-terminus, followed by two PH domains. However, ADAP1, unlike ADAP2, contains a putative N-terminal nuclear localization signal. The PH domains of ADAP1bind to the two second messenger molecules phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3) and inositol 1,3,4,5-tetrakisphosphate (I(1,3,4,5)P4) with identical high affinity, whereas those of ADAP2 specifically binds phosphatidylinositol 3,4-bisphosphate (PI(3,4)P2) and PI(3,4,5)P3, which are produced by activated phosphatidylinositol 3-kinase. ADAP1 is predominantly expressed in the brain neurons, while ADAP2 is broadly expressed, including the adipocytes, heart, and skeletal muscle but not in the brain. The limited distribution and high expression of ADAP1 in the brain indicates that ADAP1 is important for neuronal functions. ADAP1 has been shown to highly expressed in the neurons and plagues of Alzheimer's disease patients. In other hand, ADAP2 gene deletion has been shown to cause circulatory deficiencies and heart shape defects in zebrafish, indicating that ADAP2 has a vital role in heart development. Taken together, the hemizygous deletion of ADAP2 gene may be contributing to the cardiovascular malformation in patients with neurofibromatosis type 1 (NF1) microdeletions.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 301604812 609 QNEALALQSIRnLPGNSHCVDCDAQNPDWASLNLGALMCIECSGIHRNLgTHLSRVRSLDLDDWPPELIKVMSAIGNELA 688
Cdd:cd08844    3 RNKKRLLELLK-LPGNSVCADCGAPDPDWASYTLGIFICLNCSGVHRNL-PDISRVKSIRLDFWEDELVEFMKENGNLKA 80

                         90       100       110
                 ....*....|....*....|....*....|....*.
gi 301604812 689 NSVWEGSsqghVKPCSESPREE-----KERWIRAKY 719
Cdd:cd08844   81 KAKFEAF----VPPFYYRPQANdcdvlKEQWIRAKY 112

ArfGap with Rho-Gap domain, ANK repeat and PH domain-containing protein 2; The ARAP subfamily includes three members, ARAP1-3, and belongs to the ADP-ribosylation factor GTPase-activating proteins (Arf GAPs) family of proteins that promotes the hydrolysis of GTP bound to Arf, thereby inactivating Arf signaling. The function of Arfs is dependent on GAPs and guanine nucleotide exchange factors (GEFs), which allow Arfs to cycle between the GDP-bound and GTP-bound forms. In addition to the Arf GAP domain, ARAPs contain the SAM (sterile-alpha motif) domain, 5 pleckstrin homology (PH) domains, the Rho-GAP domain, the Ras-association domain, and ANK repeats. ARAPs show phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3)-dependent GAP activity toward Arf6. ARAPs play important roles in endocytic trafficking, cytoskeleton reorganization in response to growth factors stimulation, and focal adhesion dynamics. ARAP2 localizes to the cell periphery and on focal adhesions composed of paxillin and vinculin, and functions downstream of RhoA to regulate focal adhesion dynamics. ARAP2 is a PI(3,4,5)P3-dependent Arf6 GAP that binds RhoA-GTP, but it lacks the predicted catalytic arginine in the RhoGAP domain and does not have RhoGAP activity. ARAP2 reduces Rac1oGTP levels by reducing Arf6oGTP levels through GAP activity. AGAP2 also binds to and regulates focal adhesion kinase (FAK). Thus, ARAP2 signals through Arf6 and Rac1 to control focal adhesion morphology.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 301604812 624 NSHCVDCDAQNPDWASLNLGALMCIECSGIHRNLGTHLSRVRSLDLDD--WPPELIKVMSAIGNELANSVWEGSSQGHVK 701
Cdd:cd08856   18 NRSCADCKAPDPDWASINLCVVICKKCAGQHRSLGPKDSKVRSLKMDAsiWSNELIELFIVVGNKPANLFWAANLFSEED 97

                         90       100
                 ....*....|....*....|...
gi 301604812 702 PCSESPREEKERWIRAKYEQKLF 724
Cdd:cd08856   98 LHMDSDVEQRTPFITQKYKEGKF 120

ArfGAP domain of ASAP2 (ArfGAP2 with SH3 domain, ANK repeat and PH domain-containing protein 2); The Arf GAPs are a family of multidomain proteins with a common catalytic domain that promotes the hydrolysis of GTP bound to Arf , thereby inactivating Arf signaling. ASAP-subfamily GAPs include three members: ASAP1, ASAP2, ASAP3. The ASAP subfamily comprises Arf GAP, SH3, ANK repeat and PH domains. From the N-terminus, each member has a BAR, PH, Arf GAP, ANK repeat, and proline rich domains. Unlike ASAP3, ASAP1 and ASAP2 also have an SH3 domain at the C-terminus. ASAP1 and ASAP2 show strong GTPase-activating protein (GAP) activity toward Arf1 and Arf5 and weak activity toward Arf6. ASAP1 is a target of Src and FAK signaling that regulates focal adhesions, circular dorsal ruffles (CDR), invadopodia, and podosomes. ASAP1 GAP activity is synergistically stimulated by phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidic acid. ASAP2 is believed to function as an ArfGAP that controls ARF-mediated vesicle budding when recruited to Golgi membranes. It also functions as a substrate and downstream target for protein tyrosine kinases Pyk2 and Src, a pathway that may be involved in the regulation of vesicular transport.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 301604812 615 LQSIRNLPGNSHCVDCDAQNPDWASLNLGALMCIECSGIHRNLGTHLSRVRSLDLDDWPPELIKVMSAIGNELANSVWEG 694
Cdd:cd08849    6 ISEVQRMTGNDVCCDCGAPDPTWLSTNLGILTCIECSGIHRELGVHYSRMQSLTLDVLGTSELLLAKNIGNAGFNEIMEA 85

                         90       100       110
                 ....*....|....*....|....*....|..
gi 301604812 695 --SSQGHVKPCSESPREEKERWIRAKYEQKLF 724
Cdd:cd08849   86 clPAEDVVKPNPGSDMNARKDYITAKYIERRY 117

GIT2 GTPase activating protein for Arf; The GIT (G-protein coupled receptor kinase-interacting protein) subfamily includes GIT1 and GIT2, which have three ANK repeats, a Spa-homology domain (SHD), a coiled-coil domain and a C-terminal paxillin-binding site (PBS). The GIT1/2 proteins are GTPase-activating proteins that function as an inactivator of Arf signaling, and interact with the PIX/Cool family of Rac/Cdc42 guanine nucleotide exchange factors (GEFs). Unlike other ArfGAPs, GIT and PIX (Pak-interacting exchange factor) proteins are tightly associated to form an oligomeric complex that acts as a scaffold and signal integrator that can be recruited for multiple signaling pathways. The GIT/PIX complex functions as a signaling scaffold by binding to specific protein partners. As a result, the complex is transported to specific cellular locations. For instance, the GIT partners paxillin or integrin-alpha4 (to focal adhesions), piccolo and liprin-alpha (to synapses), and the beta-PIX partner Scribble (to epithelial cell-cell contacts and synapses). Moreover, the GIT/PIT complex functions to integrate signals from multiple GTP-binding protein and protein kinase pathways to regulate the actin cytoskeleton and thus cell polarity, adhesion and migration.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 301604812 627 CVDCDAQNPDWASLNLGALMCIECSGIHRNLGTHLSRVRSLDLDDWPPELIKVMSAIGNELANSVWEGS-------SQGH 699
Cdd:cd08847   11 CADCSTSDPRWASVNRGVLICDECCSVHRSLGRHISQVRHLKHTSWPPTLLQMVQTLYNNGANSIWEHSlldpasiMSGK 90