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 555290053   5 KLAVLGGEGTGKSALTVRFLTKRFIGEYASNFESIYKKHLCLERKQLNLEIYDPCSQTQ-KAKFSLTSELHWADGFVIVY 83
Cdd:cd04146    1 KIAVLGASGVGKSALTVRFLTKRFIGEYEPNLESLYSRQVTIDGEQVSLEIQDTPGQQQnEDPESLERSLRWADGFVLVY 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 555290053  84 DISDRSSFAFAKALIYRIREPQtshcKRAVESAVFLVGNKRDLCHVREVGWEEGQKLALENRCQFCELSAAEQSLEVEMM 163
Cdd:cd04146   81 SITDRSSFDVVSQLLQLIREIK----KRDGEIPVILVGNKADLLHSRQVSTEEGQKLALELGCLFFEVSAAENYLEVQNV 156

                        170
                 ....*....|
gi 555290053 164 FIRIIKDILI 173
Cdd:cd04146  157 FHELCREVRR 166

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 555290053   5 KLAVLGGEGTGKSALTVRFLTKRFIGEYASNFESIYKKHLCLERKQLNLEIYDPCSQTQ-KAKFSLTSELHWADGFVIVY 83
Cdd:cd04146    1 KIAVLGASGVGKSALTVRFLTKRFIGEYEPNLESLYSRQVTIDGEQVSLEIQDTPGQQQnEDPESLERSLRWADGFVLVY 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 555290053  84 DISDRSSFAFAKALIYRIREPQtshcKRAVESAVFLVGNKRDLCHVREVGWEEGQKLALENRCQFCELSAAEQSLEVEMM 163
Cdd:cd04146   81 SITDRSSFDVVSQLLQLIREIK----KRDGEIPVILVGNKADLLHSRQVSTEEGQKLALELGCLFFEVSAAENYLEVQNV 156

                        170
                 ....*....|
gi 555290053 164 FIRIIKDILI 173
Cdd:cd04146  157 FHELCREVRR 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 555290053    5 KLAVLGGEGTGKSALTVRFLTKRFIGEYAS--NFESiYKKHLCLERKQLNLEIYDPCSQTqkaKFSLTSELHW--ADGFV 80
Cdd:pfam00071   1 KLVLVGDGGVGKSSLLIRFTQNKFPEEYIPtiGVDF-YTKTIEVDGKTVKLQIWDTAGQE---RFRALRPLYYrgADGFL 76

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 555290053   81 IVYDISDRSSFAFAKALIYRIREpqtsHCKRAVesAVFLVGNKRDLCHVREVGWEEGQKLALENRCQFCELSaAEQSLEV 160
Cdd:pfam00071  77 LVYDITSRDSFENVKKWVEEILR----HADENV--PIVLVGNKCDLEDQRVVSTEEGEALAKELGLPFMETS-AKTNENV 149

                         170
                  ....*....|..
gi 555290053  161 EMMFIRIIKDIL 172
Cdd:pfam00071 150 EEAFEELAREIL 161

GTPase SAR1 family domain [General function prediction only];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 555290053   1 MNDVKLAVLGGEGTGKSALTvrfltKRFIGEYASNFES-------IYKKHLCLERKQLNLEIYDPCSQTQKAKF--SLTS 71
Cdd:COG1100    1 MGEKKIVVVGTGGVGKTSLV-----NRLVGDIFSLEKYlstngvtIDKKELKLDGLDVDLVIWDTPGQDEFRETrqFYAR 75

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 555290053  72 ELHWADGFVIVYDISDRSSFAFAKALIYRIREpqtshckRAVESAVFLVGNKRDLCHVREVGWEEGQKLAL--ENRCQFC 149
Cdd:COG1100   76 QLTGASLYLFVVDGTREETLQSLYELLESLRR-------LGKKSPIILVLNKIDLYDEEEIEDEERLKEALseDNIVEVV 148

                        170       180
                 ....*....|....*....|
gi 555290053 150 ELSAAEqSLEVEMMFIRIIK 169
Cdd:COG1100  149 ATSAKT-GEGVEELFAALAE 167

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 555290053   5 KLAVLGGEGTGKSALTVRFLTKRFIGEYASNFESIYKKHLCLERKQLNLEIYDPCSQTQ-KAKFSLTSELHWADGFVIVY 83
Cdd:cd04146    1 KIAVLGASGVGKSALTVRFLTKRFIGEYEPNLESLYSRQVTIDGEQVSLEIQDTPGQQQnEDPESLERSLRWADGFVLVY 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 555290053  84 DISDRSSFAFAKALIYRIREPQtshcKRAVESAVFLVGNKRDLCHVREVGWEEGQKLALENRCQFCELSAAEQSLEVEMM 163
Cdd:cd04146   81 SITDRSSFDVVSQLLQLIREIK----KRDGEIPVILVGNKADLLHSRQVSTEEGQKLALELGCLFFEVSAAENYLEVQNV 156

                        170
                 ....*....|
gi 555290053 164 FIRIIKDILI 173
Cdd:cd04146  157 FHELCREVRR 166

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 555290053     2 NDVKLAVLGGEGTGKSALTVRFLTKRFIGEYASNFESIYKKHLCLERKQLNLEIYDPCSQTQkakFSLTSELHW--ADGF 79
Cdd:smart00010   1 REYKLVVLGGGGVGKSALTIQFVQGHFVDEYDPTIEDSYRKQIEIDGEVCLLDILDTAGQEE---FSAMRDQYMrtGEGF 77

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 555290053    80 VIVYDISDRSSFAFAKAL---IYRIrepqtshcKRAVESAVFLVGNKRDLCHVREVGWEEGQKLALENRCQFCELSAAEQ 156
Cdd:smart00010  78 LLVYSITDRQSFEEIAKFreqILRV--------KDRDDVPIVLVGNKCDLENERVVSTEEGKELARQWGCPFLETSAKER 149

                          170
                   ....*....|....*
gi 555290053   157 SLeVEMMFIRIIKDI 171
Cdd:smart00010 150 IN-VDEAFYDLVREI 163

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 555290053    5 KLAVLGGEGTGKSALTVRFLTKRFIGEYAS--NFESiYKKHLCLERKQLNLEIYDPCSQTqkaKFSLTSELHW--ADGFV 80
Cdd:pfam00071   1 KLVLVGDGGVGKSSLLIRFTQNKFPEEYIPtiGVDF-YTKTIEVDGKTVKLQIWDTAGQE---RFRALRPLYYrgADGFL 76

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 555290053   81 IVYDISDRSSFAFAKALIYRIREpqtsHCKRAVesAVFLVGNKRDLCHVREVGWEEGQKLALENRCQFCELSaAEQSLEV 160
Cdd:pfam00071  77 LVYDITSRDSFENVKKWVEEILR----HADENV--PIVLVGNKCDLEDQRVVSTEEGEALAKELGLPFMETS-AKTNENV 149

                         170
                  ....*....|..
gi 555290053  161 EMMFIRIIKDIL 172
Cdd:pfam00071 150 EEAFEELAREIL 161

Ras-related in brain (Rab) family of small guanosine triphosphatases (GTPases); Rab GTPases form the largest family within the Ras superfamily. There are at least 60 Rab genes in the human genome, and a number of Rab GTPases are conserved from yeast to humans. Rab GTPases are small, monomeric proteins that function as molecular switches to regulate vesicle trafficking pathways. The different Rab GTPases are localized to the cytosolic face of specific intracellular membranes, where they regulate distinct steps in membrane traffic pathways. In the GTP-bound form, Rab GTPases recruit specific sets of effector proteins onto membranes. Through their effectors, Rab GTPases regulate vesicle formation, actin- and tubulin-dependent vesicle movement, and membrane fusion. 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 mask C-terminal lipid binding and promote cytosolic localization. While most unicellular organisms possess 5-20 Rab members, several have been found to possess 60 or more Rabs; for many of these Rab isoforms, homologous proteins are not found in other organisms. 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. Since crystal structures often lack C-terminal residues, the lipid modification site is not available for annotation in many of the CDs in the hierarchy, but is included where possible.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 555290053   4 VKLAVLGGEGTGKSALTVRFLTKRFIGEYASNF-ESIYKKHLCLERKQLNLEIYDPCSQTqkaKF-SLTSELHW-ADGFV 80
Cdd:cd00154    1 FKIVLIGDSGVGKTSLLLRFVDNKFSENYKSTIgVDFKSKTIEVDGKKVKLQIWDTAGQE---RFrSITSSYYRgAHGAI 77

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 555290053  81 IVYDISDRSSFAFAKALIYRIREPQTSHCKravesaVFLVGNKRDLCHVREVGWEEGQKLALENRCQFCELSAAEQSlEV 160
Cdd:cd00154   78 LVYDVTNRESFENLDKWLNELKEYAPPNIP------IILVGNKSDLEDERQVSTEEAQQFAKENGLLFFETSAKTGE-NV 150

                 ....*....
gi 555290053 161 EMMFIRIIK 169
Cdd:cd00154  151 DEAFESLAR 159

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 555290053   5 KLAVLGGEGTGKSALTVRFLTKRFIGEYASNFESIYKKHLCLERKQLNLEIYDPCSQTQkakFSLTSE--LHWADGFVIV 82
Cdd:cd04145    4 KLVVVGGGGVGKSALTIQFIQSYFVTDYDPTIEDSYTKQCEIDGQWARLDILDTAGQEE---FSAMREqyMRTGEGFLLV 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 555290053  83 YDISDRSSFafakALIYRIREpQTSHCKRAVESAVFLVGNKRDLCHVREVGWEEGQKLALENRCQFCELSaAEQSLEVEM 162
Cdd:cd04145   81 FSVTDRGSF----EEVDKFHT-QILRVKDRDEFPMILVGNKADLEHQRQVSREEGQELARQLKIPYIETS-AKDRVNVDK 154

                        170
                 ....*....|
gi 555290053 163 MF---IRIIK 169
Cdd:cd04145  155 AFhdlVRVIR 164

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 555290053     4 VKLAVLGGEGTGKSALTVRFLTKRFIGEYAS----NFESiykKHLCLERKQLNLEIYDPCSQtqkAKF-SLTSELHW-AD 77
Cdd:smart00175   1 FKIILIGDSGVGKSSLLSRFTDGKFSEQYKStigvDFKT---KTIEVDGKRVKLQIWDTAGQ---ERFrSITSSYYRgAV 74

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 555290053    78 GFVIVYDISDRSSFAFAKALIYRIREpqtsHCKRAVesAVFLVGNKRDLCHVREVGWEEGQKLALENRCQFCELSAAEqS 157
Cdd:smart00175  75 GALLVYDITNRESFENLENWLKELRE----YASPNV--VIMLVGNKSDLEEQRQVSREEAEAFAEEHGLPFFETSAKT-N 147

                          170
                   ....*....|....*
gi 555290053   158 LEVEMMFIRIIKDIL 172
Cdd:smart00175 148 TNVEEAFEELAREIL 162

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 555290053   3 DVKLAVLGGEGTGKSALTVRFLTKRFIGEYASNFESIYKKHLCLERKQLNLEIYDPCSQTQkakFSLTSELHWAD--GFV 80
Cdd:cd04175    1 EYKLVVLGSGGVGKSALTVQFVQGIFVEKYDPTIEDSYRKQVEVDGQQCMLEILDTAGTEQ---FTAMRDLYMKNgqGFV 77

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 555290053  81 IVYDISDRSSFAFAKALiyriREpQTSHCKRAVESAVFLVGNKRDLCHVREVGWEEGQKLALENRCQFCELSaAEQSLEV 160
Cdd:cd04175   78 LVYSITAQSTFNDLQDL----RE-QILRVKDTEDVPMILVGNKCDLEDERVVGKEQGQNLARQWGCAFLETS-AKAKINV 151

                        170
                 ....*....|.
gi 555290053 161 EMMFIRIIKDI 171
Cdd:cd04175  152 NEIFYDLVRQI 162

Ras-like protein in all tissues (Rit), Ras-like protein in neurons (Rin) and Ras-related protein which interacts with calmodulin (Ric); Rit (Ras-like protein in all tissues), Rin (Ras-like protein in neurons) and Ric (Ras-related protein which interacts with calmodulin) form a subfamily with several unique structural and functional characteristics. These proteins all lack a the C-terminal CaaX lipid-binding motif typical of Ras family proteins, and Rin and Ric contain calmodulin-binding domains. Rin, which is expressed only in neurons, induces neurite outgrowth in rat pheochromocytoma cells through its association with calmodulin and its activation of endogenous Rac/cdc42. Rit, which is ubiquitously expressed in mammals, inhibits growth-factor withdrawl-mediated apoptosis and induces neurite extension in pheochromocytoma cells. Rit and Rin are both able to form a ternary complex with PAR6, a cell polarity-regulating protein, and Rac/cdc42. This ternary complex is proposed to have physiological function in processes such as tumorigenesis. Activated Ric is likely to signal in parallel with the Ras pathway or stimulate the Ras pathway at some upstream point, and binding of calmodulin to Ric may negatively regulate Ric activity.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 555290053   5 KLAVLGGEGTGKSALTVRFLTKRFIGEYASNFESIYKKHLCLERKQLNLEIYDPCSQtqkAKFSLTSE--LHWADGFVIV 82
Cdd:cd04141    4 KIVMLGAGGVGKSAVTMQFISHSFPDYHDPTIEDAYKTQARIDNEPALLDILDTAGQ---AEFTAMRDqyMRCGEGFIIC 80

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 555290053  83 YDISDRSSFAFA---KALIYRIRepqtshckRAVESAVFLVGNKRDLCHVREVGWEEGQKLALENRCQFCELSAA 154
Cdd:cd04141   81 YSVTDRHSFQEAsefKELITRVR--------LTEDIPLVLVGNKVDLEQQRQVTTEEGRNLAREFNCPFFETSAA 147

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 555290053   4 VKLAVLGGEGTGKSALTVRFLTKRFIGEYASNFESIYKKHLCLERKQLNLEIYDPCSQTQKAkfSLTSELHWA-DGFVIV 82
Cdd:cd04139    1 HKVIMVGSGGVGKSALTLQFMYDEFVEDYEPTKADSYRKKVVLDGEEVQLNILDTAGQEDYA--AIRDNYFRSgEGFLLV 78

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 555290053  83 YDISDRSSFafakALIYRIREpQTSHCKRAVESAVFLVGNKRDLCHVREVGWEEGQKLALENRCQFCELSaAEQSLEVEM 162
Cdd:cd04139   79 FSITDMESF----TALAEFRE-QILRVKEDDNVPLLLVGNKCDLEDKRQVSVEEAANLAEQWGVNYVETS-AKTRANVDK 152

                 ....*....
gi 555290053 163 MFIRIIKDI 171
Cdd:cd04139  153 VFFDLVREI 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 555290053   3 DVKLAVLGGEGTGKSALTVRFLTKRFIGEYASNFESIYKKHLCLERKQLNLEIYDPCSQTQkakFSLTSELHW--ADGFV 80
Cdd:cd04177    1 DYKIVVLGAGGVGKSALTVQFVQNVFIESYDPTIEDSYRKQVEIDGRQCDLEILDTAGTEQ---FTAMRELYIksGQGFL 77

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 555290053  81 IVYDISDRSSFAFAKALiyriREpQTSHCKRAVESAVFLVGNKRDLCHVREVGWEEGQKLALE-NRCQFCELSAAEQSlE 159
Cdd:cd04177   78 LVYSVTSEASLNELGEL----RE-QVLRIKDSDNVPMVLVGNKADLEDDRQVSREDGVSLSQQwGNVPFYETSARKRT-N 151

                        170
                 ....*....|...
gi 555290053 160 VEMMFIRIIKDIL 172
Cdd:cd04177  152 VDEVFIDLVRQII 164

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 555290053   5 KLAVLGGEGTGKSALTVRFLTKRFIGEYASNFESIYKKHLCLERKQLNLEIYDPCSQTQkakFSLTSE--LHWADGFVIV 82
Cdd:cd04138    3 KLVVVGAGGVGKSALTIQLIQNHFVDEYDPTIEDSYRKQVVIDGETCLLDILDTAGQEE---YSAMRDqyMRTGEGFLCV 79

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 555290053  83 YDISDRSSFafakALIYRIREpQTSHCKRAVESAVFLVGNKRDLCHvREVGWEEGQKLALENRCQFCELSaAEQSLEVEM 162
Cdd:cd04138   80 FAINSRKSF----EDIHTYRE-QIKRVKDSDDVPMVLVGNKCDLAA-RTVSTRQGQDLAKSYGIPYIETS-AKTRQGVEE 152

                 ....*....
gi 555290053 163 MFIRIIKDI 171
Cdd:cd04138  153 AFYTLVREI 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 555290053   5 KLAVLGGEGTGKSALTVRFLTKRFIGEYAS----NFESiykKHLCLERKQLNLEIYDPCSQTqkaKF-----SLTSELHW 75
Cdd:cd01861    2 KLVFLGDQSVGKTSIITRFMYDTFDNQYQAtigiDFLS---KTMYVDDKTVRLQLWDTAGQE---RFrslipSYIRDSSV 75

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 555290053  76 AdgfVIVYDISDRSSFAFAKALIYRIREpqtshcKRAVESAVFLVGNKRDLCHVREVGWEEGQKLALENRCQFCELSAAE 155
Cdd:cd01861   76 A---VVVYDITNRQSFDNTDKWIDDVRD------ERGNDVIIVLVGNKTDLSDKRQVSTEEGEKKAKENNAMFIETSAKA 146

                        170
                 ....*....|....*.
gi 555290053 156 qSLEVEMMFIRIIKDI 171
Cdd:cd01861  147 -GHNVKQLFKKIAQAL 161

Rab-related GTPase family includes Rab5 and Rab22; regulates early endosome fusion; The Rab5-related subfamily includes Rab5 and Rab22 of mammals, Ypt51/Ypt52/Ypt53 of yeast, and RabF of plants. The members of this subfamily are involved in endocytosis and endocytic-sorting pathways. In mammals, Rab5 GTPases localize to early endosomes and regulate fusion of clathrin-coated vesicles to early endosomes and fusion between early endosomes. In yeast, Ypt51p family members similarly regulate membrane trafficking through prevacuolar compartments. 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 555290053   4 VKLAVLGGEGTGKSALTVRFlTKrfiGEYASNFES-----IYKKHLCLERKQLNLEIYDPCSQTqkaKF-SLTSeLHW-- 75
Cdd:cd01860    2 FKLVLLGDSSVGKSSIVLRF-VK---NEFSENQEStigaaFLTQTVNLDDTTVKFEIWDTAGQE---RYrSLAP-MYYrg 73

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 555290053  76 ADGFVIVYDISDRSSFAFAKALIYRIREPQTSHCkravesAVFLVGNKRDLCHVREVGWEEGQKLALENRCQFCELSA 153
Cdd:cd01860   74 AAAAIVVYDITSEESFEKAKSWVKELQEHGPPNI------VIALAGNKADLESKRQVSTEEAQEYADENGLLFMETSA 145

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 555290053   5 KLAVLGGEGTGKSALTVRFLTKRF-------IG-EYASnfesiykKHLCLERKQLNLEIYDPCSQTqkaKF-SLTSELH- 74
Cdd:cd01868    5 KIVLIGDSGVGKSNLLSRFTRNEFnldskstIGvEFAT-------RTIQIDGKTIKAQIWDTAGQE---RYrAITSAYYr 74

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 555290053  75 WADGFVIVYDISDRSSFAFAKALIYRIREpqtsHCKRAVesAVFLVGNKRDLCHVREVGWEEGQKLALENRCQFCELSAA 154
Cdd:cd01868   75 GAVGALLVYDITKKSTFENVERWLKELRD----HADSNI--VIMLVGNKSDLRHLRAVPTEEAKAFAEKNGLSFIETSAL 148

                        170
                 ....*....|....*..
gi 555290053 155 EqSLEVEMMFIRIIKDI 171
Cdd:cd01868  149 D-GTNVEEAFKQLLTEI 164

Rab GTPase; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 555290053   5 KLAVLGGEGTGKSALTVRFLTKRFIGEYASNFESIY-KKHLCLERKQLNLEIYDPCSQTQKAkfSLTSELH-WADGFVIV 82
Cdd:PLN03110  14 KIVLIGDSGVGKSNILSRFTRNEFCLESKSTIGVEFaTRTLQVEGKTVKAQIWDTAGQERYR--AITSAYYrGAVGALLV 91

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 555290053  83 YDISDRSSFAFAKALIYRIREPQTSHCkravesAVFLVGNKRDLCHVREVGWEEGQKLALENRCQFCELSAAEqSLEVEM 162
Cdd:PLN03110  92 YDITKRQTFDNVQRWLRELRDHADSNI------VIMMAGNKSDLNHLRSVAEEDGQALAEKEGLSFLETSALE-ATNVEK 164

                 ....*....
gi 555290053 163 MFIRIIKDI 171
Cdd:PLN03110 165 AFQTILLEI 173