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 768023118    24 QEEWPDAKDWSLQDTDAFVLVYDICSPDSFDYVKALRQRIAETRpaGAPEAPILVVGNKRDRQRLRFGPRRALAALVRRg 103
Cdd:smart00173  58 QEEFSAMRDQYMRTGEGFLLVYSITDRQSFEEIKKFREQILRVK--DRDDVPIVLVGNKCDLESERVVSTEEGKELARQ- 134

                           90       100
                   ....*....|....*....|....*
gi 768023118   104 WRCGYLECSAKYNWHVLRLFRELLR 128
Cdd:smart00173 135 WGCPFLETSAKERVNVDEAFYDLVR 159

Ras-like protein; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768023118  24 QEEWPDAKDWSLQDTDAFVLVYDICSPDSFDYVKALRQRIaeTRPAGAPEAPILVVGNKRDRQRLR---FGPRRALAalv 100
Cdd:PTZ00369  63 QEEYSAMRDQYMRTGQGFLCVYSITSRSSFEEIASFREQI--LRVKDKDRVPMILVGNKCDLDSERqvsTGEGQELA--- 137

                         90       100
                 ....*....|....*....|....*...
gi 768023118 101 rRGWRCGYLECSAKYNWHVLRLFRELLR 128
Cdd:PTZ00369 138 -KSFGIPFLETSAKQRVNVDEAFYELVR 164

Rat sarcoma (Ras) family of small guanosine triphosphatases (GTPases); The Ras family of the Ras superfamily includes classical N-Ras, H-Ras, and K-Ras, as well as R-Ras, Rap, Ral, Rheb, Rhes, ARHI, RERG, Rin/Rit, RSR1, RRP22, Ras2, Ras-dva, and RGK proteins. Ras proteins regulate cell growth, proliferation and differentiation. Ras is activated by guanine nucleotide exchange factors (GEFs) that release GDP and allow GTP binding. Many RasGEFs have been identified. These 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: among the best characterized are the Raf kinases, phosphatidylinositol 3-kinase (PI3K), RalGEFs 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 768023118  24 QEEWPDAKDWSLQDTDAFVLVYDICSPDSFDYVKALRQRIAETRpaGAPEAPILVVGNKRDRQRLRFGPRRALAALVRRg 103
Cdd:cd00876   57 QEEFSAMRDQYIRNGDGFILVYSITSRESFEEIKNIREQILRVK--DKEDVPIVLVGNKCDLENERQVSTEEGEALAEE- 133

                         90       100
                 ....*....|....*....|....*..
gi 768023118 104 WRCGYLECSAKYNWHVLRLFRELLRCA 130
Cdd:cd00876  134 WGCPFLETSAKTNINIDELFNTLVREI 160

Ras-related and Estrogen-Regulated Growth inhibitor (RERG) and Ras-like 11 (RasL11)-like families; RERG (Ras-related and Estrogen- Regulated Growth inhibitor) and Ras-like 11 are members of a novel subfamily of Ras that were identified based on their behavior in breast and prostate tumors, respectively. RERG expression was decreased or lost in a significant fraction of primary human breast tumors that lack estrogen receptor and are correlated with poor clinical prognosis. Elevated RERG expression correlated with favorable patient outcome in a breast tumor subtype that is positive for estrogen receptor expression. In contrast to most Ras proteins, RERG overexpression inhibited the growth of breast tumor cells in vitro and in vivo. RasL11 was found to be ubiquitously expressed in human tissue, but down-regulated in prostate tumors. Both RERG and RasL11 lack the C-terminal CaaX prenylation motif, where a = an aliphatic amino acid and X = any amino acid, and are localized primarily in the cytoplasm. Both are believed to have tumor suppressor activity.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768023118  34 SLQDTDAFVLVYDICSPDSFDYVKALRQRIAETRPAgAPEAPILVVGNKRDRQRLR-----FGPRRALAAlvrrgwRCGY 108
Cdd:cd04146   69 SLRWADGFVLVYSITDRSSFDVVSQLLQLIREIKKR-DGEIPVILVGNKADLLHSRqvsteEGQKLALEL------GCLF 141

                         90       100
                 ....*....|....*....|.
gi 768023118 109 LECSAKYNWH-VLRLFRELLR 128
Cdd:cd04146  142 FEVSAAENYLeVQNVFHELCR 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 768023118  24 QEEWPDAKDWSLQDTDAFVLVYDICSPDSFDYVKALRQRIAETRPAGAPEAPILVVGNKRDRQRLRFGPRRALAALVRRg 103
Cdd:cd04144   57 QEEYTALRDQWIREGEGFILVYSITSRSTFERVERFREQIQRVKDESAADVPIMIVGNKCDKVYEREVSTEEGAALARR- 135

                         90       100
                 ....*....|....*....|....*
gi 768023118 104 WRCGYLECSAKYNWHVLRLFRELLR 128
Cdd:cd04144  136 LGCEFIEASAKTNVNVERAFYTLVR 160

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 768023118  40 AFVLVYDICSPDSFDYVKALRQRIAETRPAGAPEAPILVVGNKRDRQRLRFGPRRALAALVRRgWRCGYLECSAKYNWHV 119
Cdd:cd04140   75 AFILVYSITSKQSLEELKPIYELICEIKGNNLEKIPIMLVGNKCDESPSREVSSSEGAALART-WNCAFMETSAKTNHNV 153

                 ....*...
gi 768023118 120 LRLFRELL 127
Cdd:cd04140  154 QELFQELL 161

Ras Homolog Enriched in Brain (RheB) is a small GTPase; Rheb (Ras Homolog Enriched in Brain) subfamily. Rheb was initially identified in rat brain, where its expression is elevated by seizures or by long-term potentiation. It is expressed ubiquitously, with elevated levels in muscle and brain. Rheb functions as an important mediator between the tuberous sclerosis complex proteins, TSC1 and TSC2, and the mammalian target of rapamycin (TOR) kinase to stimulate cell growth. TOR kinase regulates cell growth by controlling nutrient availability, growth factors, and the energy status of the cell. TSC1 and TSC2 form a dimeric complex that has tumor suppressor activity, and TSC2 is a GTPase activating protein (GAP) for Rheb. The TSC1/TSC2 complex inhibits the activation of TOR kinase through Rheb. Rheb has also been shown to induce the formation of large cytoplasmic vacuoles in a process that is dependent on the GTPase cycle of Rheb, but independent of the TOR kinase, suggesting Rheb plays a role in endocytic trafficking that leads to cell growth and cell-cycle progression. 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 768023118  41 FVLVYDICSPDSFDYVKALRQRIAETRpaGAPEAPILVVGNKRDRQRLRFGPR---RALAalvrRGWRCGYLECSAKYNW 117
Cdd:cd04137   76 YILVYSVTSRKSFEVVKVIYDKILDML--GKESVPIVLVGNKSDLHMERQVSAeegKKLA----ESWGAAFLESSAKENE 149

                         90
                 ....*....|.
gi 768023118 118 HVLRLFRELLR 128
Cdd:cd04137  150 NVEEAFELLIE 160

Rap2 family GTPase consists of Rap2a, Rap2b, and Rap2c; The Rap2 subgroup is part of the Rap subfamily of the Ras family. It consists of Rap2a, Rap2b, and Rap2c. Both isoform 3 of the human mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) and Traf2- and Nck-interacting kinase (TNIK) are putative effectors of Rap2 in mediating the activation of c-Jun N-terminal kinase (JNK) to regulate the actin cytoskeleton. In human platelets, Rap2 was shown to interact with the cytoskeleton by binding the actin filaments. In embryonic Xenopus development, Rap2 is necessary for the Wnt/beta-catenin signaling pathway. The Rap2 interacting protein 9 (RPIP9) is highly expressed in human breast carcinomas and correlates with a poor prognosis, suggesting a role for Rap2 in breast cancer oncogenesis. Rap2b, but not Rap2a, Rap2c, Rap1a, or Rap1b, is expressed in human red blood cells, where it is believed to be involved in vesiculation. A number of additional effector proteins for Rap2 have been identified, including the RalGEFs RalGDS, RGL, and Rlf, which also interact with Rap1 and Ras. 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 768023118  25 EEWPDAKDWSLQDTDAFVLVYDICSPDSFDYVKALRQRIaeTRPAGAPEAPILVVGNKRD---RQRLRFGPRRALAALvr 101
Cdd:cd04176   60 EQFASMRDLYIKNGQGFIVVYSLVNQQTFQDIKPMRDQI--VRVKGYEKVPIILVGNKVDlesEREVSSAEGRALAEE-- 135

                         90       100
                 ....*....|....*....|....*..
gi 768023118 102 rgWRCGYLECSAKYNWHVLRLFRELLR 128
Cdd:cd04176  136 --WGCPFMETSAKSKTMVNELFAEIVR 160

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 768023118  22 WVQEEWPDAKDWSLQDTDAFVLVYDICSPDSFDYVKALRQRIAETRPagAPEAPILVVGNKRDRQRLRFGPR---RALAA 98
Cdd:cd04148   57 WEQEDGMWLEDSCMQVGDAYVIVYSVTDRSSFEKASELRIQLRRARQ--AEDIPIILVGNKSDLVRSREVSVqegRACAV 134

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|...
gi 768023118  99 LvrrgWRCGYLECSAKYNWHVLRLFRELLRcaLVRARPAHPALRLQGALHPAR 151
Cdd:cd04148  135 V----FDCKFIETSAALQHNVDELFEGIVR--QVRLRRDSKEKNTRRMASRKR 181

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 768023118  25 EEWPDAKDWSLQDTDAFVLVYDICSPDSFDYVKALRQRIaeTRPAGAPEAPILVVGNKRDRQRLRFGPRRALAALVRRgW 104
Cdd:cd04175   60 EQFTAMRDLYMKNGQGFVLVYSITAQSTFNDLQDLREQI--LRVKDTEDVPMILVGNKCDLEDERVVGKEQGQNLARQ-W 136

                         90       100
                 ....*....|....*....|....
gi 768023118 105 RCGYLECSAKYNWHVLRLFRELLR 128
Cdd:cd04175  137 GCAFLETSAKAKINVNEIFYDLVR 160

R-Ras2/TC21, M-Ras/R-Ras3; The M-Ras/R-Ras-like subfamily contains R-Ras2/TC21, M-Ras/R-Ras3, and related members of the Ras family. M-Ras is expressed in lympho-hematopoetic cells. It interacts with some of the known Ras effectors, but appears to also have its own effectors. Expression of mutated M-Ras leads to transformation of several types of cell lines, including hematopoietic cells, mammary epithelial cells, and fibroblasts. Overexpression of M-Ras is observed in carcinomas from breast, uterus, thyroid, stomach, colon, kidney, lung, and rectum. In addition, expression of a constitutively active M-Ras mutant in murine bone marrow induces a malignant mast cell leukemia that is distinct from the monocytic leukemia induced by H-Ras. TC21, along with H-Ras, has been shown to regulate the branching morphogenesis of ureteric bud cell branching in mice. 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 768023118  24 QEEWPDAKDWSLQDTDAFVLVYDICSPDSFDYVKALRQRIaeTRPAGAPEAPILVVGNKRDRQRLRFGPRRALAALVRRg 103
Cdd:cd04145   60 QEEFSAMREQYMRTGEGFLLVFSVTDRGSFEEVDKFHTQI--LRVKDRDEFPMILVGNKADLEHQRQVSREEGQELARQ- 136

                         90       100
                 ....*....|....*....|....*
gi 768023118 104 WRCGYLECSAKYNWHVLRLFRELLR 128
Cdd:cd04145  137 LKIPYIETSAKDRVNVDKAFHDLVR 161

Rab subfamily of small GTPases; Rab GTPases are implicated in vesicle trafficking.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768023118    39 DAFVLVYDICSPDSFDYVKALRQRIAETRPagaPEAPILVVGNKRDRQRLRFGPRRALAALVRRGwRCGYLECSAKYNWH 118
Cdd:smart00175  74 VGALLVYDITNRESFENLENWLKELREYAS---PNVVIMLVGNKSDLEEQRQVSREEAEAFAEEH-GLPFFETSAKTNTN 149

                           90
                   ....*....|
gi 768023118   119 VLRLFRELLR 128
Cdd:smart00175 150 VEEAFEELAR 159

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 768023118  24 QEEWPDAKDWSLQDTDAFVLVYDICSPDSFDYVKALRQRIAetRPAGAPEAPILVVGNKRDRQRLRFGPRRALAALVRRg 103
Cdd:cd04139   58 QEDYAAIRDNYFRSGEGFLLVFSITDMESFTALAEFREQIL--RVKEDDNVPLLLVGNKCDLEDKRQVSVEEAANLAEQ- 134

                         90       100
                 ....*....|....*....|....*
gi 768023118 104 WRCGYLECSAKYNWHVLRLFRELLR 128
Cdd:cd04139  135 WGVNYVETSAKTRANVDKVFFDLVR 159

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 768023118  24 QEEWPDAKDWSLQDTDAFVLVYDICSPDSFDYVKALRQRIaeTRPAGAPEAPILVVGNKRDRQRLRFGPRRALAalVRRG 103
Cdd:cd04138   59 QEEYSAMRDQYMRTGEGFLCVFAINSRKSFEDIHTYREQI--KRVKDSDDVPMVLVGNKCDLAARTVSTRQGQD--LAKS 134

                         90       100
                 ....*....|....*....|....*
gi 768023118 104 WRCGYLECSAKYNWHVLRLFRELLR 128
Cdd:cd04138  135 YGIPYIETSAKTRQGVEEAFYTLVR 159

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 768023118  25 EEWPDAKDWSLQDTDAFVLVYDICSPDSFDYVKALRQRIaeTRPAGAPEAPILVVGNKRDRQRLRFGPRRALAALVRRGW 104
Cdd:cd04136   60 EQFTAMRDLYIKNGQGFALVYSITAQQSFNDLQDLREQI--LRVKDTEDVPMILVGNKCDLEDERVVSKEEGQNLARQWG 137

                         90       100
                 ....*....|....*....|....
gi 768023118 105 RCGYLECSAKYNWHVLRLFRELLR 128
Cdd:cd04136  138 NCPFLETSAKSKINVDEIFYDLVR 161

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 768023118  41 FVLVYDICSPDSFDYVKALRQRIaeTRPAGAPEAPILVVGNKRDRQRLRFGPRRALAALVRRGWRCGYLECSAKYNWHVL 120
Cdd:cd04177   76 FLLVYSVTSEASLNELGELREQV--LRIKDSDNVPMVLVGNKADLEDDRQVSREDGVSLSQQWGNVPFYETSARKRTNVD 153

                 ....*...
gi 768023118 121 RLFRELLR 128
Cdd:cd04177  154 EVFIDLVR 161

Rab GTPase family 7 (Rab7); Rab7 subfamily. Rab7 is a small Rab GTPase that regulates vesicular traffic from early to late endosomal stages of the endocytic pathway. The yeast Ypt7 and mammalian Rab7 are both involved in transport to the vacuole/lysosome, whereas Ypt7 is also required for homotypic vacuole fusion. Mammalian Rab7 is an essential participant in the autophagic pathway for sequestration and targeting of cytoplasmic components to the lytic compartment. Mammalian Rab7 is also proposed to function as a tumor suppressor. 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 768023118  38 TDAFVLVYDICSPDSFDYVKALRQR-IAETRPAGAPEAPILVVGNKRDRqrlrfGPRRALAALVRRGWrCG------YLE 110
Cdd:cd01862   73 ADCCVLVYDVTNPKSFESLDSWRDEfLIQASPRDPENFPFVVLGNKIDL-----EEKRQVSTKKAQQW-CKskgnipYFE 146

                         90       100
                 ....*....|....*....|.
gi 768023118 111 CSAKYNWHVLRLFRELLRCAL 131
Cdd:cd01862  147 TSAKEAINVDQAFETIARLAL 167

Ras homology family 3 (Rho3) of small guanosine triphosphatases (GTPases); Rho3 is a member of the Rho family found only in fungi. Rho3 is believed to regulate cell polarity by interacting with the diaphanous/formin family protein For3 to control both the actin cytoskeleton and microtubules. Rho3 is also believed to have a direct role in exocytosis that is independent of its role in regulating actin polarity. The function in exocytosis may be two-pronged: first, in the transport of post-Golgi vesicles from the mother cell to the bud, mediated by myosin (Myo2); second, in the docking and fusion of vesicles to the plasma membrane, mediated by an exocyst (Exo70) protein. Most Rho 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 Rho proteins.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768023118  24 QEEWPDAKDWSLQDTDAFVLVYDICSPDSFDYVKAlrQRIAETRpAGAPEAPILVVGNK---RDRQRLRFGPRRALA--- 97
Cdd:cd04134   58 QEEFDRLRSLSYADTHVIMLCFSVDNPDSLENVES--KWLAEIR-HHCPGVKLVLVALKcdlREPRNERDRGTHTISyee 134

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....
gi 768023118  98 --ALVRRGWRCGYLECSAKYNWHVLRLFRELLRCALVrARPAHP 139
Cdd:cd04134  135 glAVAKRINACRYLECSAKLNRGVNEAFTEAARVALN-ARPPHP 177

GTPase SAR1 family domain [General function prediction only];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768023118  34 SLQDTDAFVLVYDICSPDSFDYVKALRQRIAETrpagAPEAPILVVGNKRD-RQRLRFGPRRALAALVRRGWRCGYLECS 112
Cdd:COG1100   76 QLTGASLYLFVVDGTREETLQSLYELLESLRRL----GKKSPIILVLNKIDlYDEEEIEDEERLKEALSEDNIVEVVATS 151

                         90
                 ....*....|....*.
gi 768023118 113 AKYNWHVLRLFRELLR 128
Cdd:COG1100  152 AKTGEGVEELFAALAE 167

Ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1)-like consists of Rac1, Rac2 and Rac3; The Rac1-like subfamily consists of Rac1, Rac2, and Rac3 proteins, plus the splice variant Rac1b that contains a 19-residue insertion near switch II relative to Rac1. While Rac1 is ubiquitously expressed, Rac2 and Rac3 are largely restricted to hematopoietic and neural tissues respectively. Rac1 stimulates the formation of actin lamellipodia and membrane ruffles. It also plays a role in cell-matrix adhesion and cell anoikis. In intestinal epithelial cells, Rac1 is an important regulator of migration and mediates apoptosis. Rac1 is also essential for RhoA-regulated actin stress fiber and focal adhesion complex formation. In leukocytes, Rac1 and Rac2 have distinct roles in regulating cell morphology, migration, and invasion, but are not essential for macrophage migration or chemotaxis. Rac3 has biochemical properties that are closely related to Rac1, such as effector interaction, nucleotide binding, and hydrolysis; Rac2 has a slower nucleotide association and is more efficiently activated by the RacGEF Tiam1. Both Rac1 and Rac3 have been implicated in the regulation of cell migration and invasion in human metastatic breast cancer. Most Rho 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 Rho 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 768023118  24 QEEWPDAKDWSLQDTDAFVLVYDICSPDSFDYVKAlrQRIAETRpAGAPEAPILVVGNKRD-------RQRLRfgPRRAL 96
Cdd:cd01871   59 QEDYDRLRPLSYPQTDVFLICFSLVSPASFENVRA--KWYPEVR-HHCPNTPIILVGTKLDlrddkdtIEKLK--EKKLT 133

                         90       100       110
                 ....*....|....*....|....*....|....*....
gi 768023118  97 AALVRRGWRCG-------YLECSAKYNWHVLRLFRELLR 128
Cdd:cd01871  134 PITYPQGLAMAkeigavkYLECSALTQRGLKTVFDEAIR 172

Ras homology family 2 (Rho2) of small guanosine triphosphatases (GTPases); Rho2 is a fungal GTPase that plays a role in cell morphogenesis, control of cell wall integrity, control of growth polarity, and maintenance of growth direction. Rho2 activates the protein kinase C homolog Pck2, and Pck2 controls Mok1, the major (1-3) alpha-D-glucan synthase. Together with Rho1 (RhoA), Rho2 regulates the construction of the cell wall. Unlike Rho1, Rho2 is not an essential protein, but its overexpression is lethal. Most Rho 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 proper intracellular localization via membrane attachment. As with other Rho family GTPases, the GDP/GTP cycling is regulated by GEFs (guanine nucleotide exchange factors), GAPs (GTPase-activating proteins) and GDIs (guanine nucleotide dissociation inhibitors).

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768023118  24 QEEWPDAKDWSLQDTDAFVLVYDICSPDSFDYVkalRQRIAETRPAGAPEAPILVVGNKRD-RQRLRFGPRRALAALVRR 102
Cdd:cd04129   59 QEEYERLRPLSYSKAHVILIGFAIDTPDSLENV---RTKWIEEVRRYCPNVPVILVGLKKDlRQEAVAKGNYATDEFVPI 135

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|
gi 768023118 103 ----------GWRcGYLECSAKYNWHVLRLFRELLRCALV 132
Cdd:cd04129  136 qqaklvaraiGAK-KYMECSALTGEGVDDVFEAATRAALL 174

Rab GTPase family J-like (RabJ-like); RJLs are found in many protists and as chimeras with C-terminal DNAJ domains in deuterostome metazoa. They are not found in plants, fungi, and protostome metazoa, suggesting a horizontal gene transfer between protists and deuterostome metazoa. RJLs lack any known membrane targeting signal and contain a degenerate phosphate/magnesium-binding 3 (PM3) motif, suggesting an impaired ability to hydrolyze GTP. 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.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 768023118  37 DTDAFVLVYDICSPDSFDYVKA-LRQRIAETRPAGAPEAPILVV-GNKRDRQRLR 89
Cdd:cd04119   72 DTQGVLLVYDVTDRQSFEALDSwLKEMKQEGGPHGNMENIVVVVcANKIDLTKHR 126

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 768023118  42 VLVYDICSPDSFDYVKALRQRIAETrpaGAPEAPILVVGNKRDRQRLRFGPRRALAALVRRgWRCGYLECSAKYNWHVLR 121
Cdd:cd01867   80 ILVYDITDEKSFENIKNWMRNIDEH---ASEDVERMLVGNKCDMEEKRVVSKEEGEALARE-YGIKFLETSAKANINVEE 155

                 ....*..
gi 768023118 122 LFRELLR 128
Cdd:cd01867  156 AFLTLAK 162

Rab GTPase family 30 (Rab30); Rab30 subfamily. Rab30 appears to be associated with the Golgi stack. It is expressed in a wide variety of tissue types and in humans maps to chromosome 11. 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 768023118  40 AFVLVYDICSPDSFDyvkALRQRIAETRPAGAPEAPILVVGNKRDRQRLRFGPRRaLAALVRRGWRCGYLECSAKYNWHV 119
Cdd:cd04114   82 ALILTYDITCEESFR---CLPEWLREIEQYANNKVITILVGNKIDLAERREVSQQ-RAEEFSDAQDMYYLETSAKESDNV 157

                 ....*..
gi 768023118 120 LRLFREL 126
Cdd:cd04114  158 EKLFLDL 164

Rab GTPase family 40 (Rab40) contains Rab40a, Rab40b and Rab40c; The Rab40 subfamily contains Rab40a, Rab40b, and Rab40c, which are all highly homologous. In rat, Rab40c is localized to the perinuclear recycling compartment (PRC), and is distributed in a tissue-specific manor, with high expression in brain, heart, kidney, and testis, low expression in lung and liver, and no expression in spleen and skeletal muscle. Rab40c is highly expressed in differentiated oligodendrocytes but minimally expressed in oligodendrocyte progenitors, suggesting a role in the vesicular transport of myelin components. Unlike most other Ras-superfamily proteins, Rab40c was shown to have a much lower affinity for GTP, and an affinity for GDP that is lower than for GTP. 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 768023118  42 VLVYDICSPDSFDYVKALRQRIAETrpagAPEAPILVVGNkrdrqRLRFGPRRALAALVRRGW--RCG--YLECSAKYNW 117
Cdd:cd04121   83 ILVYDITNRWSFDGIDRWIKEIDEH----APGVPKILVGN-----RLHLAFKRQVATEQAQAYaeRNGmtFFEVSPLCNF 153

                         90
                 ....*....|....*.
gi 768023118 118 HVLRLFRELLRCALVR 133
Cdd:cd04121  154 NITESFTELARIVLMR 169

Rab GTPase families 18 (Rab18) and 32 (Rab32); Rab38/Rab32 subfamily. Rab32 and Rab38 are members of the Rab family of small GTPases. Human Rab32 was first identified in platelets but it is expressed in a variety of cell types, where it functions as an A-kinase anchoring protein (AKAP). Rab38 has been shown to be melanocyte-specific. 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 768023118  40 AFVlVYDICSPDSFDYVKALRQRIAE--TRPAGAPeAPILVVGNKRDRQRLR-FGPRRALAALVRRGWRCGYLECSAKYN 116
Cdd:cd04107   77 AII-VFDVTRPSTFEAVLKWKADLDSkvTLPNGEP-IPALLLANKCDLKKERlAKDPEQMDQFCKENGFIGWFETSAKEN 154

                         90
                 ....*....|....*
gi 768023118 117 WHVLRLFRELLRCAL 131
Cdd:cd04107  155 INIEEAMRFLVKNIL 169

ADP-ribosylation factor(Arf)/Arf-like (Arl) small GTPases; Arf (ADP-ribosylation factor)/Arl (Arf-like) small GTPases. Arf proteins are activators of phospholipase D isoforms. Unlike Ras proteins they lack cysteine residues at their C-termini and therefore are unlikely to be prenylated. Arfs are N-terminally myristoylated. Members of the Arf family are regulators of vesicle formation in intracellular traffic that interact reversibly with membranes of the secretory and endocytic compartments in a GTP-dependent manner. They depart from other small GTP-binding proteins by a unique structural device, interswitch toggle, that implements front-back communication from N-terminus to the nucleotide binding site. Arf-like (Arl) proteins are close relatives of the Arf, but only Arl1 has been shown to function in membrane traffic like the Arf proteins. Arl2 has an unrelated function in the folding of native tubulin, and Arl4 may function in the nucleus. Most other Arf family proteins are so far relatively poorly characterized. Thus, despite their significant sequence homologies, Arf family proteins may regulate unrelated functions.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|
gi 768023118  36 QDTDAFVLVYDICSPDSFDYVK-ALRQRIAETRPAGAPeapILVVGNKRD 84
Cdd:cd00878   65 ENTDGLIFVVDSSDRERIEEAKnELHKLLNEEELKGAP---LLILANKQD 111

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 768023118  37 DTDAFVLVYDICSPDSFDYVkalRQRIAETRPAGAPEAPILVVGNKRDRQRLRFGPRRALAALVRRgWRCGYLECSAKYN 116
Cdd:cd01861   72 DSSVAVVVYDITNRQSFDNT---DKWIDDVRDERGNDVIIVLVGNKTDLSDKRQVSTEEGEKKAKE-NNAMFIETSAKAG 147

                         90
                 ....*....|
gi 768023118 117 WHVLRLFREL 126
Cdd:cd01861  148 HNVKQLFKKI 157