Rem, Rem2, Rad, Gem/Kir (RGK) subfamily of Ras GTPases; RGK subfamily. The RGK (Rem, Rem2, Rad, Gem/Kir) subfamily of Ras GTPases are expressed in a tissue-specific manner and are dynamically regulated by transcriptional and posttranscriptional mechanisms in response to environmental cues. RGK proteins bind to the beta subunit of L-type calcium channels, causing functional down-regulation of these voltage-dependent calcium channels, and either termination of calcium-dependent secretion or modulation of electrical conduction and contractile function. Inhibition of L-type calcium channels by Rem2 may provide a mechanism for modulating calcium-triggered exocytosis in hormone-secreting cells, and has been proposed to influence the secretion of insulin in pancreatic beta cells. RGK proteins also interact with and inhibit the Rho/Rho kinase pathway to modulate remodeling of the cytoskeleton. Two characteristics of RGK proteins cited in the literature are N-terminal and C-terminal extensions beyond the GTPase domain typical of Ras superfamily members. The N-terminal extension is not conserved among family members; the C-terminal extension is reported to be conserved among the family and lack the CaaX prenylation motif typical of membrane-associated Ras proteins. However, a putative CaaX motif has been identified in the alignment of the C-terminal residues of this CD.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1597523150  86 YRVVLIGEQGVGKSTLANIFAGvHDSMDSDCEVLGEDTYERTLIVDGESATIILLDMWENKGeNEWLQDHCMQVGDAYLI 165
Cdd:cd04148     1 YRVVLLGDSGVGKSSLANIFTA-GVYEDSAYEASGDDTYERTVSVDGEEATLVVYDHWEQED-GMWLEDSCMQVGDAYVI 78

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1597523150 166 VYSITDRASFEKASELRIQLRRARQTEDIPIILVGNKSDLVRCREVSISEGRACAVVFDCKFIETSAAVQHNVKELFEGI 245
Cdd:cd04148    79 VYSVTDRSSFEKASELRIQLRRARQAEDIPIILVGNKSDLVRSREVSVQEGRACAVVFDCKFIETSAALQHNVDELFEGI 158

                         170       180       190       200       210       220
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1597523150 246 VRQVRLRRDSKEKNERRLAYQKRRESIPRKARRFWGKIVAKNNKNMAFKLKSKSCHDLSVL 306
Cdd:cd04148   159 VRQVRLRRDSKEKNTRRMASRKRRESITKKAKRFLSKIVAKNNKGMAFKQKSKSCHDLSVL 219

Rem, Rem2, Rad, Gem/Kir (RGK) subfamily of Ras GTPases; RGK subfamily. The RGK (Rem, Rem2, Rad, Gem/Kir) subfamily of Ras GTPases are expressed in a tissue-specific manner and are dynamically regulated by transcriptional and posttranscriptional mechanisms in response to environmental cues. RGK proteins bind to the beta subunit of L-type calcium channels, causing functional down-regulation of these voltage-dependent calcium channels, and either termination of calcium-dependent secretion or modulation of electrical conduction and contractile function. Inhibition of L-type calcium channels by Rem2 may provide a mechanism for modulating calcium-triggered exocytosis in hormone-secreting cells, and has been proposed to influence the secretion of insulin in pancreatic beta cells. RGK proteins also interact with and inhibit the Rho/Rho kinase pathway to modulate remodeling of the cytoskeleton. Two characteristics of RGK proteins cited in the literature are N-terminal and C-terminal extensions beyond the GTPase domain typical of Ras superfamily members. The N-terminal extension is not conserved among family members; the C-terminal extension is reported to be conserved among the family and lack the CaaX prenylation motif typical of membrane-associated Ras proteins. However, a putative CaaX motif has been identified in the alignment of the C-terminal residues of this CD.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1597523150  86 YRVVLIGEQGVGKSTLANIFAGvHDSMDSDCEVLGEDTYERTLIVDGESATIILLDMWENKGeNEWLQDHCMQVGDAYLI 165
Cdd:cd04148     1 YRVVLLGDSGVGKSSLANIFTA-GVYEDSAYEASGDDTYERTVSVDGEEATLVVYDHWEQED-GMWLEDSCMQVGDAYVI 78

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1597523150 166 VYSITDRASFEKASELRIQLRRARQTEDIPIILVGNKSDLVRCREVSISEGRACAVVFDCKFIETSAAVQHNVKELFEGI 245
Cdd:cd04148    79 VYSVTDRSSFEKASELRIQLRRARQAEDIPIILVGNKSDLVRSREVSVQEGRACAVVFDCKFIETSAALQHNVDELFEGI 158

                         170       180       190       200       210       220
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1597523150 246 VRQVRLRRDSKEKNERRLAYQKRRESIPRKARRFWGKIVAKNNKNMAFKLKSKSCHDLSVL 306
Cdd:cd04148   159 VRQVRLRRDSKEKNTRRMASRKRRESITKKAKRFLSKIVAKNNKGMAFKQKSKSCHDLSVL 219

Ras family; Includes sub-families Ras, Rab, Rac, Ral, Ran, Rap Ypt1 and more. Shares P-loop motif with GTP_EFTU, arf and myosin_head. See pfam00009 pfam00025, pfam00063. As regards Rab GTPases, these are important regulators of vesicle formation, motility and fusion. They share a fold in common with all Ras GTPases: this is a six-stranded beta-sheet surrounded by five alpha-helices.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1597523150  87 RVVLIGEQGVGKSTLA-----NIFAGVHDSmdsdceVLGEDTYERTLIVDGEsatIILLDMWENKGENEW--LQDHCMQV 159
Cdd:pfam00071   1 KLVLVGDGGVGKSSLLirftqNKFPEEYIP------TIGVDFYTKTIEVDGK---TVKLQIWDTAGQERFraLRPLYYRG 71

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1597523150 160 GDAYLIVYSITDRASFEKASELRIQLRRARQtEDIPIILVGNKSDLVRCREVSISEGRACAVVFDCKFIETSAAVQHNVK 239
Cdd:pfam00071  72 ADGFLLVYDITSRDSFENVKKWVEEILRHAD-ENVPIVLVGNKCDLEDQRVVSTEEGEALAKELGLPFMETSAKTNENVE 150

                         170
                  ....*....|.
gi 1597523150 240 ELFEGIVRQVR 250
Cdd:pfam00071 151 EAFEELAREIL 161

GTPase SAR1 family domain [General function prediction only];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1597523150  87 RVVLIGEQGVGKSTLANIFAGVHDSMDSDCEVLGEDTYERTLIVDGESATIILLDMwenKGENE----------WLQDHc 156
Cdd:COG1100     5 KIVVVGTGGVGKTSLVNRLVGDIFSLEKYLSTNGVTIDKKELKLDGLDVDLVIWDT---PGQDEfretrqfyarQLTGA- 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1597523150 157 mqvgDAYLIVYSITDRASFEKASELRIQLRRARqtEDIPIILVGNKSDLVRCREVsISEGRACAVVFDCKF---IETSAA 233
Cdd:COG1100    81 ----SLYLFVVDGTREETLQSLYELLESLRRLG--KKSPIILVLNKIDLYDEEEI-EDEERLKEALSEDNIvevVATSAK 153

                         170       180
                  ....*....|....*....|....
gi 1597523150 234 VQHNVKELFEGIVRQVRLRRDSKE 257
Cdd:COG1100   154 TGEGVEELFAALAEILRGEGDSLD 177

Rem, Rem2, Rad, Gem/Kir (RGK) subfamily of Ras GTPases; RGK subfamily. The RGK (Rem, Rem2, Rad, Gem/Kir) subfamily of Ras GTPases are expressed in a tissue-specific manner and are dynamically regulated by transcriptional and posttranscriptional mechanisms in response to environmental cues. RGK proteins bind to the beta subunit of L-type calcium channels, causing functional down-regulation of these voltage-dependent calcium channels, and either termination of calcium-dependent secretion or modulation of electrical conduction and contractile function. Inhibition of L-type calcium channels by Rem2 may provide a mechanism for modulating calcium-triggered exocytosis in hormone-secreting cells, and has been proposed to influence the secretion of insulin in pancreatic beta cells. RGK proteins also interact with and inhibit the Rho/Rho kinase pathway to modulate remodeling of the cytoskeleton. Two characteristics of RGK proteins cited in the literature are N-terminal and C-terminal extensions beyond the GTPase domain typical of Ras superfamily members. The N-terminal extension is not conserved among family members; the C-terminal extension is reported to be conserved among the family and lack the CaaX prenylation motif typical of membrane-associated Ras proteins. However, a putative CaaX motif has been identified in the alignment of the C-terminal residues of this CD.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1597523150  86 YRVVLIGEQGVGKSTLANIFAGvHDSMDSDCEVLGEDTYERTLIVDGESATIILLDMWENKGeNEWLQDHCMQVGDAYLI 165
Cdd:cd04148     1 YRVVLLGDSGVGKSSLANIFTA-GVYEDSAYEASGDDTYERTVSVDGEEATLVVYDHWEQED-GMWLEDSCMQVGDAYVI 78

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1597523150 166 VYSITDRASFEKASELRIQLRRARQTEDIPIILVGNKSDLVRCREVSISEGRACAVVFDCKFIETSAAVQHNVKELFEGI 245
Cdd:cd04148    79 VYSVTDRSSFEKASELRIQLRRARQAEDIPIILVGNKSDLVRSREVSVQEGRACAVVFDCKFIETSAALQHNVDELFEGI 158

                         170       180       190       200       210       220
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1597523150 246 VRQVRLRRDSKEKNERRLAYQKRRESIPRKARRFWGKIVAKNNKNMAFKLKSKSCHDLSVL 306
Cdd:cd04148   159 VRQVRLRRDSKEKNTRRMASRKRRESITKKAKRFLSKIVAKNNKGMAFKQKSKSCHDLSVL 219

Small GTPase of the Ras superfamily; ill-defined subfamily; SMART predicts Ras-like small GTPases of the ARF, RAB, RAN, RAS, and SAR subfamilies. Others that could not be classified in this way are predicted to be members of the small GTPase superfamily without predictions of the subfamily.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1597523150   86 YRVVLIGEQGVGKSTL-----ANIFAGVHDSMDsdcevlgEDTYERTLIVDGESATIILLDmweNKGENEW--LQDHCMQ 158
Cdd:smart00010   3 YKLVVLGGGGVGKSALtiqfvQGHFVDEYDPTI-------EDSYRKQIEIDGEVCLLDILD---TAGQEEFsaMRDQYMR 72

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1597523150  159 VGDAYLIVYSITDRASFEKASELRIQLRRARQTEDIPIILVGNKSDLVRCREVSISEGRACAVVFDCKFIETSAAVQHNV 238
Cdd:smart00010  73 TGEGFLLVYSITDRQSFEEIAKFREQILRVKDRDDVPIVLVGNKCDLENERVVSTEEGKELARQWGCPFLETSAKERINV 152

                          170
                   ....*....|....
gi 1597523150  239 KELFEGIVRQVRLR 252
Cdd:smart00010 153 DEAFYDLVREIRKS 166

Ras family; Includes sub-families Ras, Rab, Rac, Ral, Ran, Rap Ypt1 and more. Shares P-loop motif with GTP_EFTU, arf and myosin_head. See pfam00009 pfam00025, pfam00063. As regards Rab GTPases, these are important regulators of vesicle formation, motility and fusion. They share a fold in common with all Ras GTPases: this is a six-stranded beta-sheet surrounded by five alpha-helices.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1597523150  87 RVVLIGEQGVGKSTLA-----NIFAGVHDSmdsdceVLGEDTYERTLIVDGEsatIILLDMWENKGENEW--LQDHCMQV 159
Cdd:pfam00071   1 KLVLVGDGGVGKSSLLirftqNKFPEEYIP------TIGVDFYTKTIEVDGK---TVKLQIWDTAGQERFraLRPLYYRG 71

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1597523150 160 GDAYLIVYSITDRASFEKASELRIQLRRARQtEDIPIILVGNKSDLVRCREVSISEGRACAVVFDCKFIETSAAVQHNVK 239
Cdd:pfam00071  72 ADGFLLVYDITSRDSFENVKKWVEEILRHAD-ENVPIVLVGNKCDLEDQRVVSTEEGEALAKELGLPFMETSAKTNENVE 150

                         170
                  ....*....|.
gi 1597523150 240 ELFEGIVRQVR 250
Cdd:pfam00071 151 EAFEELAREIL 161

Ras GTPase family containing H-Ras,N-Ras and K-Ras4A/4B; H-Ras/N-Ras/K-Ras subfamily. H-Ras, N-Ras, and K-Ras4A/4B are the prototypical members of the Ras family. These isoforms generate distinct signal outputs despite interacting with a common set of activators and effectors, and are strongly associated with oncogenic progression in tumor initiation. Mutated versions of Ras that are insensitive to GAP stimulation (and are therefore constitutively active) are found in a significant fraction of human cancers. Many Ras guanine nucleotide exchange factors (GEFs) have been identified. They are sequestered in the cytosol until activation by growth factors triggers recruitment to the plasma membrane or Golgi, where the GEF colocalizes with Ras. Active (GTP-bound) Ras interacts with several effector proteins that stimulate a variety of diverse cytoplasmic signaling activities. Some are known to positively mediate the oncogenic properties of Ras, including Raf, phosphatidylinositol 3-kinase (PI3K), RalGEFs, and Tiam1. Others are proposed to play negative regulatory roles in oncogenesis, including RASSF and NORE/MST1. Most Ras proteins contain a lipid modification site at the C-terminus, with a typical sequence motif CaaX, where a = an aliphatic amino acid and X = any amino acid. Lipid binding is essential for membrane attachment, a key feature of most Ras proteins. Due to the presence of truncated sequences in this CD, the lipid modification site is not available for annotation.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1597523150  86 YRVVLIGEQGVGKSTLANIFAGVHDSMDSDCEVlgEDTYERTLIVDGESAtiiLLDMWENKGENEW--LQDHCMQVGDAY 163
Cdd:cd04138     2 YKLVVVGAGGVGKSALTIQLIQNHFVDEYDPTI--EDSYRKQVVIDGETC---LLDILDTAGQEEYsaMRDQYMRTGEGF 76

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1597523150 164 LIVYSITDRASFEKASELRIQLRRARQTEDIPIILVGNKSDLvRCREVSISEGRACAVVFDCKFIETSAAVQHNVKELFE 243
Cdd:cd04138    77 LCVFAINSRKSFEDIHTYREQIKRVKDSDDVPMVLVGNKCDL-AARTVSTRQGQDLAKSYGIPYIETSAKTRQGVEEAFY 155

                  ....*..
gi 1597523150 244 GIVRQVR 250
Cdd:cd04138   156 TLVREIR 162

Rat sarcoma (Ras) family 2 of small guanosine triphosphatases (GTPases); The Ras2 subfamily, found exclusively in fungi, was first identified in Ustilago maydis. In U. maydis, Ras2 is regulated by Sql2, a protein that is homologous to GEFs (guanine nucleotide exchange factors) of the CDC25 family. Ras2 has been shown to induce filamentous growth, but the signaling cascade through which Ras2 and Sql2 regulate cell morphology is not known. Most Ras proteins contain a lipid modification site at the C-terminus, with a typical sequence motif CaaX, where a = an aliphatic amino acid and X = any amino acid. Lipid binding is essential for membrane attachment, a key feature of most Ras proteins.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1597523150  87 RVVLIGEQGVGKSTLANIFAGVHDSMDSDCEVlgEDTYERTLIVDGESATIILLDmweNKGENEW--LQDHCMQVGDAYL 164
Cdd:cd04144     1 KLVVLGDGGVGKTALTIQLCLNHFVETYDPTI--EDSYRKQVVVDGQPCMLEVLD---TAGQEEYtaLRDQWIREGEGFI 75

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1597523150 165 IVYSITDRASFEKASELRIQLRRARQTE--DIPIILVGNKSDLVRCREVSISEGRACAVVFDCKFIETSAAVQHNVKELF 242
Cdd:cd04144    76 LVYSITSRSTFERVERFREQIQRVKDESaaDVPIMIVGNKCDKVYEREVSTEEGAALARRLGCEFIEASAKTNVNVERAF 155

                         170
                  ....*....|.
gi 1597523150 243 EGIVRQVRLRR 253
Cdd:cd04144   156 YTLVRALRQQR 166

Ral (Ras-like) family containing highly homologous RalA and RalB; The Ral (Ras-like) subfamily consists of the highly homologous RalA and RalB. Ral proteins are believed to play a crucial role in tumorigenesis, metastasis, endocytosis, and actin cytoskeleton dynamics. Despite their high sequence similarity (>80% sequence identity), nonoverlapping and opposing functions have been assigned to RalA and RalBs in tumor migration. In human bladder and prostate cancer cells, RalB promotes migration while RalA inhibits it. A Ral-specific set of GEFs has been identified that are activated by Ras binding. This RalGEF activity is enhanced by Ras binding to another of its target proteins, phosphatidylinositol 3-kinase (PI3K). Ral effectors include RLIP76/RalBP1, a Rac/cdc42 GAP, and the exocyst (Sec6/8) complex, a heterooctomeric protein complex that is involved in tethering vesicles to specific sites on the plasma membrane prior to exocytosis. In rat kidney cells, RalB is required for functional assembly of the exocyst and for localizing the exocyst to the leading edge of migrating cells. In human cancer cells, RalA is required to support anchorage-independent proliferation and RalB is required to suppress apoptosis. RalA has been shown to localize to the plasma membrane while RalB is localized to the intracellular vesicles. Most Ras proteins contain a lipid modification site at the C-terminus, with a typical sequence motif CaaX, where a = an aliphatic amino acid and X = any amino acid. Lipid binding is essential for membrane attachment, a key feature of most Ras proteins. Due to the presence of truncated sequences in this CD, the lipid modification site is not available for annotation.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1597523150  86 YRVVLIGEQGVGKSTLANIFagVHDSMDSDCEVLGEDTYERTLIVDGESatiILLDMWENKGENEW--LQDHCMQVGDAY 163
Cdd:cd04139     1 HKVIMVGSGGVGKSALTLQF--MYDEFVEDYEPTKADSYRKKVVLDGEE---VQLNILDTAGQEDYaaIRDNYFRSGEGF 75

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1597523150 164 LIVYSITDRASFEKASELRIQLRRARQTEDIPIILVGNKSDLVRCREVSISEGRACAVVFDCKFIETSAAVQHNVKELFE 243
Cdd:cd04139    76 LLVFSITDMESFTALAEFREQILRVKEDDNVPLLLVGNKCDLEDKRQVSVEEAANLAEQWGVNYVETSAKTRANVDKVFF 155

                  ....*..
gi 1597523150 244 GIVRQVR 250
Cdd:cd04139   156 DLVREIR 162

Rap-like family consists of Rap1, Rap2 and RSR1; The Rap subfamily consists of the Rap1, Rap2, and RSR1. Rap subfamily proteins perform different cellular functions, depending on the isoform and its subcellular localization. For example, in rat salivary gland, neutrophils, and platelets, Rap1 localizes to secretory granules and is believed to regulate exocytosis or the formation of secretory granules. Rap1 has also been shown to localize in the Golgi of rat fibroblasts, zymogen granules, plasma membrane, and microsomal membrane of the pancreatic acini, as well as in the endocytic compartment of skeletal muscle cells and fibroblasts. Rap1 localizes in the nucleus of human oropharyngeal squamous cell carcinomas (SCCs) and cell lines. Rap1 plays a role in phagocytosis by controlling the binding of adhesion receptors (typically integrins) to their ligands. In yeast, Rap1 has been implicated in multiple functions, including activation and silencing of transcription and maintenance of telomeres. Rap2 is involved in multiple functions, including activation of c-Jun N-terminal kinase (JNK) to regulate the actin cytoskeleton and activation of the Wnt/beta-catenin signaling pathway in embryonic Xenopus. A number of effector proteins for Rap2 have been identified, including isoform 3 of the human mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) and Traf2- and Nck-interacting kinase (TNIK), and the RalGEFs RalGDS, RGL, and Rlf, which also interact with Rap1 and Ras. RSR1 is the fungal homolog of Rap1 and Rap2. In budding yeasts, it is involved in selecting a site for bud growth, which directs the establishment of cell polarization. The Rho family GTPase Cdc42 and its GEF, Cdc24, then establish an axis of polarized growth. It is believed that Cdc42 interacts directly with RSR1 in vivo. In filamentous fungi such as Ashbya gossypii, RSR1 is a key regulator of polar growth in the hypha. Most Ras proteins contain a lipid modification site at the C-terminus, with a typical sequence motif CaaX, where a = an aliphatic amino acid and X = any amino acid. Lipid binding is essential for membrane attachment, a key feature of most Ras proteins. Due to the presence of truncated sequences in this CD, the lipid modification site is not available for annotation.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1597523150  86 YRVVLIGEQGVGKSTLANIFA-GVH-DSMDSDCEvlgeDTYERTLIVDGESATIILLDmweNKGENEW--LQDHCMQVGD 161
Cdd:cd04136     2 YKLVVLGSGGVGKSALTVQFVqGIFvDKYDPTIE----DSYRKQIEVDCQQCMLEILD---TAGTEQFtaMRDLYIKNGQ 74

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1597523150 162 AYLIVYSITDRASFEKASELRIQLRRARQTEDIPIILVGNKSDLVRCREVSISEGRACAVVF-DCKFIETSAAVQHNVKE 240
Cdd:cd04136    75 GFALVYSITAQQSFNDLQDLREQILRVKDTEDVPMILVGNKCDLEDERVVSKEEGQNLARQWgNCPFLETSAKSKINVDE 154

                  ....*....
gi 1597523150 241 LFEGIVRQV 249
Cdd:cd04136   155 IFYDLVRQI 163

A Ras homolog member I (ARHI); ARHI (A Ras homolog member I) is a member of the Ras family with several unique structural and functional properties. ARHI is expressed in normal human ovarian and breast tissue, but its expression is decreased or eliminated in breast and ovarian cancer. ARHI contains an N-terminal extension of 34 residues (human) that is required to retain its tumor suppressive activity. Unlike most other Ras family members, ARHI is maintained in the constitutively active (GTP-bound) state in resting cells and has modest GTPase activity. ARHI inhibits STAT3 (signal transducers and activators of transcription 3), a latent transcription factor whose abnormal activation plays a critical role in oncogenesis. Most Ras proteins contain a lipid modification site at the C-terminus, with a typical sequence motif CaaX, where a = an aliphatic amino acid and X = any amino acid. Lipid binding is essential for membrane attachment, a key feature of most Ras proteins. Due to the presence of truncated sequences in this CD, the lipid modification site is not available for annotation.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1597523150  86 YRVVLIGEQGVGKSTLANIFagVHDSMDSDCEVLGEDTYERTLivdGESATIILLDMWENKGENEW--LQDHCMQVGDAY 163
Cdd:cd04140     2 YRVVVFGAGGVGKSSLVLRF--VKGTFRESYIPTIEDTYRQVI---SCSKSICTLQITDTTGSHQFpaMQRLSISKGHAF 76

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1597523150 164 LIVYSITDRASFEKASELRIQLRRAR--QTEDIPIILVGNKSDLVRCREVSISEGRACAVVFDCKFIETSAAVQHNVKEL 241
Cdd:cd04140    77 ILVYSITSKQSLEELKPIYELICEIKgnNLEKIPIMLVGNKCDESPSREVSSSEGAALARTWNCAFMETSAKTNHNVQEL 156

                  ..
gi 1597523150 242 FE 243
Cdd:cd04140   157 FQ 158

Rap1 family GTPase consists of Rap1a and Rap1b isoforms; The Rap1 subgroup is part of the Rap subfamily of the Ras family. It can be further divided into the Rap1a and Rap1b isoforms. In humans, Rap1a and Rap1b share 95% sequence homology, but are products of two different genes located on chromosomes 1 and 12, respectively. Rap1a is sometimes called smg p21 or Krev1 in the older literature. Rap1 proteins are believed to perform different cellular functions, depending on the isoform, its subcellular localization, and the effector proteins it binds. For example, in rat salivary gland, neutrophils, and platelets, Rap1 localizes to secretory granules and is believed to regulate exocytosis or the formation of secretory granules. Rap1 has also been shown to localize in the Golgi of rat fibroblasts, zymogen granules, plasma membrane, and the microsomal membrane of pancreatic acini, as well as in the endocytic compartment of skeletal muscle cells and fibroblasts. High expression of Rap1 has been observed in the nucleus of human oropharyngeal squamous cell carcinomas (SCCs) and cell lines; interestingly, in the SCCs, the active GTP-bound form localized to the nucleus, while the inactive GDP-bound form localized to the cytoplasm. Rap1 plays a role in phagocytosis by controlling the binding of adhesion receptors (typically integrins) to their ligands. In yeast, Rap1 has been implicated in multiple functions, including activation and silencing of transcription and maintenance of telomeres. Rap1a, which is stimulated by T-cell receptor (TCR) activation, is a positive regulator of T cells by directing integrin activation and augmenting lymphocyte responses. In murine hippocampal neurons, Rap1b determines which neurite will become the axon and directs the recruitment of Cdc42, which is required for formation of dendrites and axons. In murine platelets, Rap1b is required for normal homeostasis in vivo and is involved in integrin activation. Most Ras proteins contain a lipid modification site at the C-terminus, with a typical sequence motif CaaX, where a = an aliphatic amino acid and X = any amino acid. Lipid binding is essential for membrane attachment, a key feature of most Ras proteins. Due to the presence of truncated sequences in this CD, the lipid modification site is not available for annotation.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1597523150  86 YRVVLIGEQGVGKSTLA-----NIFAGVHDSMDsdcevlgEDTYERTLIVDGESATIILLDmweNKGENEW--LQDHCMQ 158
Cdd:cd04175     2 YKLVVLGSGGVGKSALTvqfvqGIFVEKYDPTI-------EDSYRKQVEVDGQQCMLEILD---TAGTEQFtaMRDLYMK 71

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1597523150 159 VGDAYLIVYSITDRASFEKASELRIQLRRARQTEDIPIILVGNKSDLVRCREVSISEGRACAVVFDCKFIETSAAVQHNV 238
Cdd:cd04175    72 NGQGFVLVYSITAQSTFNDLQDLREQILRVKDTEDVPMILVGNKCDLEDERVVGKEQGQNLARQWGCAFLETSAKAKINV 151

                         170
                  ....*....|.
gi 1597523150 239 KELFEGIVRQV 249
Cdd:cd04175   152 NEIFYDLVRQI 162

RSR1/Bud1p family GTPase; RSR1/Bud1p is a member of the Rap subfamily of the Ras family that is found in fungi. In budding yeasts, RSR1 is involved in selecting a site for bud growth on the cell cortex, which directs the establishment of cell polarization. The Rho family GTPase cdc42 and its GEF, cdc24, then establish an axis of polarized growth by organizing the actin cytoskeleton and secretory apparatus at the bud site. It is believed that cdc42 interacts directly with RSR1 in vivo. In filamentous fungi, polar growth occurs at the tips of hypha and at novel growth sites along the extending hypha. In Ashbya gossypii, RSR1 is a key regulator of hyphal growth, localizing at the tip region and regulating in apical polarization of the actin cytoskeleton. Most Ras proteins contain a lipid modification site at the C-terminus, with a typical sequence motif CaaX, where a = an aliphatic amino acid and X = any amino acid. Lipid binding is essential for membrane attachment, a key feature of most Ras proteins.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1597523150  86 YRVVLIGEQGVGKSTLANIFagVHDSMDSDCEVLGEDTYERTLIVDGESATIILLDmweNKGENEW--LQDHCMQVGDAY 163
Cdd:cd04177     2 YKIVVLGAGGVGKSALTVQF--VQNVFIESYDPTIEDSYRKQVEIDGRQCDLEILD---TAGTEQFtaMRELYIKSGQGF 76

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1597523150 164 LIVYSITDRASFEKASELRIQLRRARQTEDIPIILVGNKSDLVRCREVSISEGRACAVVF-DCKFIETSAAVQHNVKELF 242
Cdd:cd04177    77 LLVYSVTSEASLNELGELREQVLRIKDSDNVPMVLVGNKADLEDDRQVSREDGVSLSQQWgNVPFYETSARKRTNVDEVF 156

                  ....*...
gi 1597523150 243 EGIVRQVR 250
Cdd:cd04177   157 IDLVRQII 164

Rab GTPase family 21 (Rab21); The localization and function of Rab21 are not clearly defined, with conflicting data reported. Rab21 has been reported to localize in the ER in human intestinal epithelial cells, with partial colocalization with alpha-glucosidase, a late endosomal/lysosomal marker. More recently, Rab21 was shown to colocalize with and affect the morphology of early endosomes. In Dictyostelium, GTP-bound Rab21, together with two novel LIM domain proteins, LimF and ChLim, has been shown to regulate phagocytosis. GTPase activating proteins (GAPs) interact with GTP-bound Rab and accelerate the hydrolysis of GTP to GDP. Guanine nucleotide exchange factors (GEFs) interact with GDP-bound Rabs to promote the formation of the GTP-bound state. Rabs are further regulated by guanine nucleotide dissociation inhibitors (GDIs), which facilitate Rab recycling by masking C-terminal lipid binding and promoting cytosolic localization. Most Rab GTPases contain a lipid modification site at the C-terminus, with sequence motifs CC, CXC, or CCX. Lipid binding is essential for membrane attachment, a key feature of most Rab proteins. Due to the presence of truncated sequences in this CD, the lipid modification site is not available for annotation.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1597523150  86 YRVVLIGEQGVGKSTLANIFagVHDSMDSDCEVLGEDT-YERTLIVDGESATiilLDMWENKGENEWlqdHCM-----QV 159
Cdd:cd04123     1 FKVVLLGEGRVGKTSLVLRY--VENKFNEKHESTTQASfFQKTVNIGGKRID---LAIWDTAGQERY---HALgpiyyRD 72

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1597523150 160 GDAYLIVYSITDRASFEKASELRIQLRRARQtEDIPIILVGNKSDLVRCREVSISEGRACAVVFDCKFIETSAAVQHNVK 239
Cdd:cd04123    73 ADGAILVYDITDADSFQKVKKWIKELKQMRG-NNISLVIVGNKIDLERQRVVSKSEAEEYAKSVGAKHFETSAKTGKGIE 151

                         170
                  ....*....|
gi 1597523150 240 ELFEGIVRQV 249
Cdd:cd04123   152 ELFLSLAKRM 161

Rab GTPase family 6 (Rab6); Rab6 is involved in microtubule-dependent transport pathways through the Golgi and from endosomes to the Golgi. Rab6A of mammals is implicated in retrograde transport through the Golgi stack, and is also required for a slow, COPI-independent, retrograde transport pathway from the Golgi to the endoplasmic reticulum (ER). This pathway may allow Golgi residents to be recycled through the ER for scrutiny by ER quality-control systems. Yeast Ypt6p, the homolog of the mammalian Rab6 GTPase, is not essential for cell viability. Ypt6p acts in endosome-to-Golgi, in intra-Golgi retrograde transport, and possibly also in Golgi-to-ER trafficking. GTPase activating proteins (GAPs) interact with GTP-bound Rab and accelerate the hydrolysis of GTP to GDP. Guanine nucleotide exchange factors (GEFs) interact with GDP-bound Rabs to promote the formation of the GTP-bound state. Rabs are further regulated by guanine nucleotide dissociation inhibitors (GDIs), which facilitate Rab recycling by masking C-terminal lipid binding and promoting cytosolic localization. Most Rab GTPases contain a lipid modification site at the C-terminus, with sequence motifs CC, CXC, or CCX. Lipid binding is essential for membrane attachment, a key feature of most Rab proteins. Due to the presence of truncated sequences in this CD, the lipid modification site is not available for annotation.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1597523150  86 YRVVLIGEQGVGKSTLANIFagVHDSMDsdcevlgeDTYERTLIVDGESATI------ILLDMWENKGENE-------WL 152
Cdd:cd01861     1 HKLVFLGDQSVGKTSIITRF--MYDTFD--------NQYQATIGIDFLSKTMyvddktVRLQLWDTAGQERfrslipsYI 70

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1597523150 153 QDHCMQVgdaylIVYSITDRASFEKASELrIQLRRARQTEDIPIILVGNKSDLVRCREVSISEGRACAVVFDCKFIETSA 232
Cdd:cd01861    71 RDSSVAV-----VVYDITNRQSFDNTDKW-IDDVRDERGNDVIIVLVGNKTDLSDKRQVSTEEGEKKAKENNAMFIETSA 144

                         170
                  ....*....|...
gi 1597523150 233 AVQHNVKELFEGI 245
Cdd:cd01861   145 KAGHNVKQLFKKI 157

Rab GTPase family 11 (Rab11)-like includes Rab11a, Rab11b, and Rab25; Rab11a, Rab11b, and Rab25 are closely related, evolutionary conserved Rab proteins that are differentially expressed. Rab11a is ubiquitously synthesized, Rab11b is enriched in brain and heart and Rab25 is only found in epithelia. Rab11/25 proteins seem to regulate recycling pathways from endosomes to the plasma membrane and to the trans-Golgi network. Furthermore, Rab11a is thought to function in the histamine-induced fusion of tubulovesicles containing H+, K+ ATPase with the plasma membrane in gastric parietal cells and in insulin-stimulated insertion of GLUT4 in the plasma membrane of cardiomyocytes. Overexpression of Rab25 has recently been observed in ovarian cancer and breast cancer, and has been correlated with worsened outcomes in both diseases. In addition, Rab25 overexpression has also been observed in prostate cancer, transitional cell carcinoma of the bladder, and invasive breast tumor cells. GTPase activating proteins (GAPs) interact with GTP-bound Rab and accelerate the hydrolysis of GTP to GDP. Guanine nucleotide exchange factors (GEFs) interact with GDP-bound Rabs to promote the formation of the GTP-bound state. Rabs are further regulated by guanine nucleotide dissociation inhibitors (GDIs), which facilitate Rab recycling by masking C-terminal lipid binding and promoting cytosolic localization. Most Rab GTPases contain a lipid modification site at the C-terminus, with sequence motifs CC, CXC, or CCX. Lipid binding is essential for membrane attachment, a key feature of most Rab proteins. Due to the presence of truncated sequences in this CD, the lipid modification site is not available for annotation.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1597523150  86 YRVVLIGEQGVGKSTLANIFAGVHDSMDSDCEVlGEDTYERTLIVDGEsatIILLDMWENKGenewlQDHCMQVGDAY-- 163
Cdd:cd01868     4 FKIVLIGDSGVGKSNLLSRFTRNEFNLDSKSTI-GVEFATRTIQIDGK---TIKAQIWDTAG-----QERYRAITSAYyr 74

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1597523150 164 -----LIVYSITDRASFEKA----SELRiqlrrARQTEDIPIILVGNKSDLVRCREVSISEGRACAVVFDCKFIETSAAV 234
Cdd:cd01868    75 gavgaLLVYDITKKSTFENVerwlKELR-----DHADSNIVIMLVGNKSDLRHLRAVPTEEAKAFAEKNGLSFIETSALD 149

                         170
                  ....*....|....*
gi 1597523150 235 QHNVKELFEGIVRQV 249
Cdd:cd01868   150 GTNVEEAFKQLLTEI 164

Rab GTPase family 39 (Rab39); Found in eukaryotes, Rab39 is mainly found in epithelial cell lines, but is distributed widely in various human tissues and cell lines. It is believed to be a novel Rab protein involved in regulating Golgi-associated vesicular transport during cellular endocytosis. GTPase activating proteins (GAPs) interact with GTP-bound Rab and accelerate the hydrolysis of GTP to GDP. Guanine nucleotide exchange factors (GEFs) interact with GDP-bound Rabs to promote the formation of the GTP-bound state. Rabs are further regulated by guanine nucleotide dissociation inhibitors (GDIs), which facilitate Rab recycling by masking C-terminal lipid binding and promoting cytosolic localization. Most Rab GTPases contain a lipid modification site at the C-terminus, with sequence motifs CC, CXC, or CCX. Lipid binding is essential for membrane attachment, a key feature of most Rab proteins.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1597523150  86 YRVVLIGEQGVGKSTLAN-----IFAGVHDSmdsdceVLGEDTYERTliVDGESATIILLDMWENKGenewlQDHCMQVG 160
Cdd:cd04111     3 FRLIVIGDSTVGKSSLLKrftegRFAEVSDP------TVGVDFFSRL--IEIEPGVRIKLQLWDTAG-----QERFRSIT 69

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1597523150 161 DAY-------LIVYSITDRASFEKASELRIQLRRARQTEDIPIILVGNKSDLVRCREVSISEGRACAVVFDCKFIETSAA 233
Cdd:cd04111    70 RSYyrnsvgvLLVFDITNRESFEHVHDWLEEARSHIQPHRPVFILVGHKCDLESQRQVTREEAEKLAKDLGMKYIETSAR 149

                         170       180
                  ....*....|....*....|....
gi 1597523150 234 VQHNVKELFEGIVRQVRLRRDSKE 257
Cdd:cd04111   150 TGDNVEEAFELLTQEIYERIKRGE 173

Rab GTPase families 8, 10, 13 (Rab8, Rab10, Rab13); Rab8/Sec4/Ypt2 are known or suspected to be involved in post-Golgi transport to the plasma membrane. It is likely that these Rabs have functions that are specific to the mammalian lineage and have no orthologs in plants. Rab8 modulates polarized membrane transport through reorganization of actin and microtubules, induces the formation of new surface extensions, and has an important role in directed membrane transport to cell surfaces. The Ypt2 gene of the fission yeast Schizosaccharomyces pombe encodes a member of the Ypt/Rab family of small GTP-binding proteins, related in sequence to Sec4p of Saccharomyces cerevisiae but closer to mammalian Rab8. GTPase activating proteins (GAPs) interact with GTP-bound Rab and accelerate the hydrolysis of GTP to GDP. Guanine nucleotide exchange factors (GEFs) interact with GDP-bound Rabs to promote the formation of the GTP-bound state. Rabs are further regulated by guanine nucleotide dissociation inhibitors (GDIs), which facilitate Rab recycling by masking C-terminal lipid binding and promoting cytosolic localization. Most Rab GTPases contain a lipid modification site at the C-terminus, with sequence motifs CC, CXC, or CCX. Lipid binding is essential for membrane attachment, a key feature of most Rab proteins. Due to the presence of truncated sequences in this CD, the lipid modification site is not available for annotation.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1597523150  86 YRVVLIGEQGVGKSTLanIFAGVHDSM-DSDCEVLGEDTYERTLIVDGESatiILLDMWENKGenewlQDHCMQVGDAY- 163
Cdd:cd01867     4 FKLLLIGDSGVGKSCL--LLRFSEDSFnPSFISTIGIDFKIRTIELDGKK---IKLQIWDTAG-----QERFRTITTSYy 73

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1597523150 164 ------LIVYSITDRASFEkasELRIQLRRARQ--TEDIPIILVGNKSDLVRCREVSISEGRACAVVFDCKFIETSAAVQ 235
Cdd:cd01867    74 rgamgiILVYDITDEKSFE---NIKNWMRNIDEhaSEDVERMLVGNKCDMEEKRVVSKEEGEALAREYGIKFLETSAKAN 150

                         170
                  ....*....|....*..
gi 1597523150 236 HNVKELFEGIVRQVRLR 252
Cdd:cd01867   151 INVEEAFLTLAKDILKK 167

Rab GTPase; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1597523150  86 YRVVLIGEQGVGKSTLANIFAGVHDSMDSDcEVLGEDTYERTLIVDGESatiILLDMWENKGenewlQDHCMQVGDAY-- 163
Cdd:PLN03110   13 FKIVLIGDSGVGKSNILSRFTRNEFCLESK-STIGVEFATRTLQVEGKT---VKAQIWDTAG-----QERYRAITSAYyr 83

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1597523150 164 -----LIVYSITDRASFEKASELriqLRRARQTED--IPIILVGNKSDLVRCREVSISEGRACAVVFDCKFIETSAAVQH 236
Cdd:PLN03110   84 gavgaLLVYDITKRQTFDNVQRW---LRELRDHADsnIVIMMAGNKSDLNHLRSVAEEDGQALAEKEGLSFLETSALEAT 160