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RASSF6 (Ras association (RalGDS/AF-6) domain family member 6)

Written2010-04Luke B Hesson, Farida Latif
Lowy Cancer Centre, Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, NSW2052, Australia (LBH); School of Clinical, Experimental Medicine, College of Medical, Dental Sciences, Department of Medical, Molecular Genetics, University of Birmingham, Birmingham B15 2TT, UK (FL)

(Note : for Links provided by Atlas : click)

Identity

Alias_namesRas association (RalGDS/AF-6) domain family member 6
Other aliasDKFZp686K23225
HGNC (Hugo) RASSF6
LocusID (NCBI) 166824
Atlas_Id 43462
Location 4q13.3  [Link to chromosome band 4q13]
Location_base_pair Starts at 73571550 and ends at 73620570 bp from pter ( according to hg19-Feb_2009)  [Mapping RASSF6.png]
Local_order Centromere-AFP-AFM-RASSF6-IL8-Telomere.
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
IGF2BP2 (3q27.2) / RASSF6 (4q13.3)
Note Brief overview
The RASSF family of tumour suppressor genes (TSG) encode Ras superfamily effector proteins that, amongst other functions, mediate some of the growth inhibitory functions of Ras proteins. Several members of this family are inactivated by promoter DNA hypermethylation in a broad range of cancers, and the RASSF6 gene may be a frequent target of epigenetic inactivation in leukaemias. The RASSF6 protein is involved in the regulation of apoptosis partly by controlling the function of the proapoptotic mammalian serine/threonine kinases 1 and 2 (MST1 and MST2) and modulator of apoptosis 1 (MOAP-1).

DNA/RNA

 
  Figure 1: RASSF6 gene structure. The RASSF6 gene is composed of at least two isoforms that are transcribed from immediately upstream (RASSF6A) or from within (RASSF6B) a small CpG island.
Description The RASSF6 gene occupies 47478 bp of genomic DNA. RASSF6A [GenBank:NM_201431] contains 11 exons and is transcribed 82 bp upstream from a small (214 bp) 5' CpG island (at chr4:74,486,045-74,486,258). RASSF6B [GenBank:NM_177532] contains 11 exons and is transcribed from within the same CpG island. There is evidence of additional splice variants and transcription initiation sites for the RASSF6 gene, however these have not been validated.

Protein

Description RASSF6A [GenBank:NP_958834] is a 369 amino acid protein whereas RASSF6B [GenBank:NP_803876] is a 337 amino acid protein. The RASSF6A protein (figure 2) contains C-terminal Ras-association (RA) and Sav/RASSF/Hpo (SARAH) domains that define the 'classical' RASSF family (RASSF1, RASSF2, RASSF3, RASSF4, RASSF5, RASSF6). The RASSF6B protein lacks the N-terminal 32 amino acids present in RASSF6A but is otherwise identical. There are some inconsistencies in the literature regarding which may be the major isoform, however all functional work to date has studied the larger 369 amino acid protein, which is hereafter referred to as RASSF6. Using an in-house antibody Ikeda et al., (2007) were unable to detect endogenous RASSF6 protein. All functional work has been performed using overexpressed RASSF6 protein. A commercially available antibody towards RASSF6 (ProteinTech Group) has been used to demonstrate re-expression following treatment with the DNA demethylating agent 5-aza-2'deoxycytidine (5azaDC) and Trichostatin A (TSA) in leukaemia cell lines in which RASSF6 is epigenetically inactivated (Hesson et al., 2009).
 
  Figure 2: RASSF6 transcript and protein structure. The RASSF6A mRNA (red bar) encodes a 369 amino acid protein [GenBank:NP_958834] containing a C-terminal Ras-association (RA) domain of the RalGDS/AF-6 variety and acidic coiled-coil Sav/RASSF/Hpo (SARAH) domain. RASSF6B [GenBank:NP_803876] is a predicted 337 amino acid protein lacking the N-terminal 32 amino acids present in RASSF6A.
Expression Northern blotting of a normal tissue RNA panel shows RASSF6 mRNA is highly expressed in thymus, kidney and placenta, with lower levels of expression in colon, small intestine and lung (Allen et al., 2007). In the same study the matched normal tissue from a primary tumour cDNA panel showed readily detectable levels of RASSF6 expression in rectal, pancreatic, liver, breast and stomach tissues. There has been no systematic analysis of the expression patterns of the different RASSF6 isoforms. RT-PCR analysis of a range of tumour cell lines showed that RASSF6 is highly expressed in HeLa and A549 cells with lower levels observed in MCF-7, U373, H1299 and HepG2 (Ikeda et al., 2007). It appears from these studies that the tissue distribution of RASSF6 expression is much more restricted than that of the RASSF members RASSF1, RASSF2 and RASSF5.
Expression of the RASSF6 gene is lost or downregulated in a variety of solid tumours by unknown mechanisms, whereas in childhood leukaemias RASSF6 is inactivated by CpG island promoter region DNA methylation (see below).
Function dRASSF antagonises the Hippo pathway
In Drosophila, dRASSF represents the orthologue of mammalian RASSF1-6. dRASSF protein competes with Salvador (the Drosophila orthologue of the mammalian WW45 protein) for binding to Hippo (the Drosophila orthologue of the mammalian MST kinases). The dRASSF-Hippo and Salvador-Hippo interactions appear mutually exclusive and control Hippo function in very different ways. Both Salvador or dRASSF are stabilised following binding to Hippo, however, probing of immunoprecipitates of Salvador or dRASSF with a phospho-specific antibody that recognises active Hippo demonstrates that Hippo is present in Drosophila cells in two pools; an active form associated with Salvador and an inactive form associated with dRASSF (Polesello et al., 2006). Furthermore, RNAi-mediated dRASSF depletion led to a marked increase in Hippo activation following Staurosporine (STS) treatment, a potent activator of Hippo in Drosophila cells and MSTs in mammalian cells. Thus, in Drosophila dRASSF restricts the activation of Hippo, which may account for the smaller size of dRASSF mutant flies (Polesello et al., 2006).

Regulation of apoptosis by mammalian RASSF6
Several studies have demonstrated that overexpression of RASSF6 induces apoptosis and inhibits the growth of a variety of tumour cell lines (Ikeda et al., 2007; Allen et al., 2007; Ikeda et al., 2009). In HeLa cells RASSF6-induced apoptosis occurred through both caspase-dependent and caspase-independent pathways, since overexpression of RASSF6 results in cleavage and activation of caspase-3 but apoptosis was not abrogated by z-VAD-FMK, an inhibitor of caspase-1, caspase-3, caspase-4 and caspase-7 activation (Ikeda et al., 2007). RASSF6 also induced Bax activation and cytochrome C release as well as the release of apoptosis-inducing factor (AIF) and endonuclease G (endoG) from the mitochondria. Following release from the mitochondria AIF and endoG may result in DNA fragmentation even in the absence of caspase activation. Early evidence has suggested that the molecular mechanisms of RASSF6-induced apoptosis are likely to be complex and multi-layered. Currently, three signalling routes are implicated in RASSF6-induced apoptosis (see below), though at present it is unclear whether these routes act autonomously or as part of an extensive apoptotic network.

RASSF6 is an effector molecule of K-Ras-mediated apoptosis
RASSF6 interacts with K-Ras in a GTP-dependent manner via its Ras-association domain and the effector domain of K-Ras. Therefore, RASSF6 exhibits the basic properties of a Ras effector protein. These data are in contradiction to another report in which RASSF6 did not interact with K-Ras, H-Ras, N-Ras, M-Ras or TC21 under the same conditions that RASSF5 binds to these Ras proteins (Ikeda et al., 2007). Apart from a strict context-dependency of these interactions The reasons for this discrepancy is unclear but may be related to a strict context-dependency of the interaction or to the requirement of Ras farnesylation as shown by Allen et al., (2007). Of particular note however, is the observation that RASSF6 acts synergistically with activated K-Ras to induce cell death in 293-T cells (Allen et al., 2007). Taken together these data suggests RASSF6 does indeed function within a K-Ras-regulated pathway, most likely through direct interaction, to determine cell fate.

RASSF6 negatively regulates the proapoptotic protein MST2
RASSF6 interacts with MST2 via the Sav/RASSF/Hpo (SARAH) domains within both proteins (Ikeda et al., 2009). It seems clear from many studies that several (if not all) classical RASSF proteins interact with the MST1 and MST2 kinases and that this interaction is at least partly involved in RASSF-induced apoptosis (van der Weyden and Adams, 2007). Ikeda et al., (2009) showed that the SARAH domain of MST2 can bind both WW45 (the mammalian orthologue of the Drosophila protein Salvador) and RASSF6 to form a trimeric complex. However, RASSF6 and WW45 do not interact. This differs somewhat with the regulation of the Hippo pathway in Drosophila, in which the Salvador/Hippo and dRASSF/Hippo complexes are mutually exclusive (see above). RASSF6 inhibits MST2 kinase activity, however activation of MST2 releases RASSF6 in a manner dependent on WW45. Previous studies have demonstrated that MST2 can extensively phosphorylate WW45 (Callus et al., 2006). Ikeda et al., (2009) demonstrated that activation of MST2 by the phosphatase inhibitor okadaic acid (OA) reduced the co-immunoprecipitation of RASSF6 with MST2, whilst the association of MST2 and WW45 remained unchanged. Taken together this suggests that the activation of MST2 and subsequent phosphorylation of WW45 results in the release of RASSF6 from the WW45/MST2/RASSF6 complex. The release of RASSF6 was shown to be WW45-dependent since RASSF6 remained in complex with MST2 following OA treatment of cells in which WW45 had been depleted by RNAi. Furthermore, the release of RASSF6 appears to be necessary for RASSF6-mediated apoptosis. However, apoptosis was vastly reduced in cells transfected with both MST2 and RASSF6. This block of RASSF6-induced apoptosis was dependent on the SARAH domain of MST2 but not the kinase activity of MST2 suggesting that MST2 blocks RASSF6-mediated apoptosis by physical interaction. Interestingly co-expression of RASSF6, MST2 and WW45 resulted in potent cell death. This effect was dependent on the SARAH domain of WW45 suggesting that physical interaction of WW45 with MST2 was necessary to reinstate RASSF6-induced apoptosis by allowing the release of RASSF6. Inhibition of MST2 kinase activity by RASSF6 also results in the inhibition of NDR1 and LATS2 phosphorylation (Ikeda et al., 2009). NDR1 and LATS2 are known MST2 substrates that form part of the MST/Hippo tumour suppressor pathway (see Hergovich and Hemmings, 2009 and Harvey and Tapon, 2007 for a more thorough review of the regulation of apoptosis through the MST/Hippo pathway). Thus release of RASSF6 from the MST2-WW45 complex allows RASSF6-mediated and MST2-mediated apoptosis (figure 3). The induction of apoptosis through these separate pathways may explain the caspase-dependent and caspase-independent nature of RASSF6-mediated apoptosis, since full activation of MSTs is thought to require caspase cleavage.

MOAP-1 is involved in RASSF6-mediated apoptosis
The MOAP-1 protein may also be a RASSF6 effector molecule. To date, two independent studies have demonstrated that RASSF6 also interacts with MOAP-1 (Allen et al., 2007; Ikeda et al., 2009). Though this interaction has not been demonstrated formally at the endogenous level, co-expression of the two proteins clearly demonstrates that MOAP-1 is a likely mediator of RASSF6-induced apoptosis in a manner independent of the MST/Hippo tumour suppressor pathway. MOAP-1 regulates the 'extrinsic' pathway of apoptosis by acting downstream of death receptors such as the tumour necrosis factor a receptor 1 (TNF-R1) and TNFa apoptosis-inducing related ligand receptor 1 (TRAIL-R1). A role for MOAP-1 in regulating RASSF1A-induced apoptosis has previously been demonstrated. Following ligand binding the C-terminal region of MOAP-1 associates with the death domain of TNF-R1. Subsequently, the TNF-R1/MOAP-1 receptor complex is internalised and recruits RASSF1A through the N-terminal cysteine-rich (C1) domain within RASSF1A (Baksh et al., 2005; Vos et al., 2006; Foley et al., 2008). Under 'static' conditions MOAP-1 is held in an inactive conformation, however binding to RASSF1A results in a conformational change that allows MOAP-1 to interact with Bax. This in turn induces a conformational change within Bax that is required for its insertion into the mitochondrial membrane and for the release of inner mitochondrial membrane proteins that can induce apoptosis. Interestingly, activated K-Ras, RASSF1A and MOAP-1 synergise to induce Bax activation and apoptosis (Vos et al., 2006) indicating that cell death induced by the RASSF1A/MOAP-1 interaction may be regulated by both K-Ras and death receptors.
The acidic sequence Glu-Glu-Glu-Glu [312EEEE] in the SARAH domain of RASSF1A that binds to MOAP-1 (Baksh et al., 2005) is also partially conserved in the RASSF6 SARAH domain [EEEK]. However, this is unlikely to be the sole site of interaction since RASSF6 lacking the N-terminal region, the Ras-association domain, or the SARAH domain also interacted with MOAP-1 (Ikeda et al., 2009). Depletion of MOAP-1 partially suppresses RASSF6-mediated apoptosis and co-expression of MST2 vastly reduces the co-immunoprecipitation of RASSF6 and MOAP-1; an effect that is abrogated by the expression of WW45. Taken together these data suggest that the MST2/WW45 complex binds RASSF6 and prevents its interaction with MOAP-1. The MST-Hippo pathway and the MOAP-1 pathway represent distinct RASSF6-regulated apoptotic pathways that are triggered fy thg qctivation of MST2 (figure 3).

 
  Figure 3: The molecular basis of RASSF6-induced apoptosis. Multiple lines of evidence suggest that RASSF6-induced apoptosis involves multiple pathways. K-Ras, MST2 and MOAP-1 have all been implicated in RASSF6-induced apoptosis. To date RASSF1, RASSF2, RASSF4, RASSF5 and RASSF6 have been shown to bind to the MST1 and MST2 kinases. Thus, the RASSF proteins play a major role in regulating apoptosis through the MST/Hippo tumour suppressor pathway leading to apoptosis. The regulation of apoptosis through activation of the TNF-R1 and TRAIL-R1 death receptor pathways has been shown to involve the interaction of RASSF1A with MOAP-1. This interaction leads to the release of inner mitochondrial membrane proteins that result in apoptosis. RASSF6 also interacts with MOAP-1, though the events downstream have not been fully elucidated. The release of inner mitochondrial membrane proteins is a major facet of RASSF6-induced apoptosis therefore it seems likely that RASSF6 regulates MOAP-1 function in a similar way to RASSF1A and may feed into the same pathway. The synergistic effects of activated K-Ras, RASSF6 and MOAP-1 overexpression suggests that apoptosis through the RASSF6/MOAP-1 complex may be at least partially K-Ras-regulated.
Homology RASSF6 is one of 10 members of the Ras-association domain family (RASSF) comprising RASSF1-10 (please refer to figure 3 of the RASSF2 gene card. RASSF1-6 are termed the 'classical' RASSF family and contain C-terminal RA and SARAH domains. Consequently, RASSF1-6 are most similar in sequence within their C-termini. RASSF7, RASSF8, RASSF9 and RASSF10 represent evolutionarily conserved but structurally distinct RASSF members that lack the SARAH domains and contain N-terminal RA domains. RASSF7-10 are termed the 'N-terminal' RASSF family. Many of these RASSF members are involved in tumourigenesis and several (RASSF1A, RASSF2, RASSF4, RASSF5A, RASSF6 and RASSF10) are inactivated in a variety of human cancers (Hesson et al., 2007; van der Weyden and Adams, 2007; Hesson et al., 2009). RASSF6 also has orthologues in several species (table 1) including Drosophila melanogaster, which is the orthologue of the human RASSF1-6 genes.
 

Mutations

Note To date no inactivating mutations to RASSF6 have been described.

Implicated in

Note
  
Entity Various cancers
Note Loss of RASSF6 expression in cancer.
Disease Northern blotting analysis showed RASSF6 expression is lost or downregulated in 30-60% of primary tumour tissues of the breast, colon, kidney, liver, pancreas, stomach and thyroid (Allen et al., 2007). The mechanisms underlying this reduced expression are not clear and, at least in solid tumours, loss of RASSF6 expression is not associated with promoter DNA methylation (Allen et al., 2007). Other mechanisms of gene silencing such as histone modifications or long-range epigenetic silencing may account for RASSF6 downregulation, but this has not been investigated. In childhood leukaemias silencing of RASSF6 expression by promoter hypermethylation appears to be an extremely frequent event and was identified in 94% (48/51) B-ALL and 41% (12/29) T-ALL (Hesson et al., 2009). To date this remains the first and only description of a mechanism accounting for the loss of RASSF6 expression in cancer but further suggests that epigenetic inactivation of RASSF6 may be specific to leukaemias. Further evidence that the loss of RASSF6 expression is important in cancer is provided in a study by Finn et al., (2007), which demonstrated downregulation of RASSF6 expression in malignant versus benign thyroid tissue.
  
  
Entity Pancreatic endocrine tumour
Note RASSF6 is downregulated in the pancreatic endocrine tumour cell line BON1 following siRNAi of Achaete-scute complex-like 1 (ASCL1), a basic helix loop helix (bHLH) transcription factor regulated by the NOTCH signalling pathway (Johansson et al., 2009). ASCL1 also negatively regulates expression of Dickkopf homologue 1 (DKK1), an antagonist of the Wnt/beta-catenin-dependent signalling pathway.
  
  
Entity Breast cancer
Note Using an in vitro model of breast carcinogenesis, human non-tumourigenic immortalised breast epithelial cell line MCF-10A cells were selected following exposure to the mutagen ICR191 to create transformed cells (Zientek-Targosz et al., 2008). One of the genes found to contain a frameshift mutation following this selection was RASSF6. The authors postulate that this indicates that inactivation of RASSF6 may be involved in the transformation of breast epithelial cells thus indicating the potential importance of RASSF6 in tumour development.
  
  
Entity Childhood B-ALL
Note RASSF6 is downregulated in mature B-cells in response to B-cell activating factor (BAFF) treatment (Saito et al., 2008). BAFF is a tumour necrosis factor (TNF) superfamily member, which is thought to be involved in the survival and maturation of B-cells partly by inhibiting apoptosis. This finding reiterates the potential importance of the frequent epigenetic inactivation of RASSF6 in childhood B-ALL (Hesson et al., 2009), which would nullify RASSF6-mediated apoptosis.
  
  
Entity Viral-induced bronchiolitis
Disease Genetic mapping studies have linked the RASSF6 locus to viral-induced bronchiolitis, the most common cause of infant hospital admissions in the industrialised world (Hull et al., 2004; Smyth and Openshaw, 2006). The 250 kb interval at 4q13.3 implicated by Hull et al., (2004) includes three genes (AFM, RASSF6 and IL8), however it is unclear which gene is the important player. The predominant cause of acute viral bronchiolitis is infection with the respiratory syncytial virus (RSV). A major consequence of RSV infection is stimulation of the NF-kappaB pathway (Hull et al., 2004), which is thought to modulate the degree of inflammation and support viral replication, perhaps by suppressing apoptosis (Bitko et al., 2004). Using an NF-kappaB luciferase reporter system in A549 lung tumour cells it has been found that RASSF6 can suppress the serum-induced basal levels of NF-kappaB reporter expression by approximately fivefold (Allen et al., 2007). Therefore, RASSF6 remains a promising susceptibility gene candidate for viral-induced bronchiolitis.
  
  
Entity Heavy metal detoxification
Note Expression of murine Rassf6 was upregulated following subcutaneous injection of Cadmium, possibly implicating Rassf6 in the cellular mechanisms of heavy metal detoxification (Wimmer et al., 2005). However, it seems equally likely that the observed upregulation of Rassf6 could be due to increased apoptosis caused by the toxic effects of heavy metal exposure.
  

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Citation

This paper should be referenced as such :
Hesson, LB ; Latif, F
RASSF6 (Ras association (RalGDS/AF-6) domain family member 6)
Atlas Genet Cytogenet Oncol Haematol. 2011;15(1):47-54.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/RASSF6ID43462ch4q13.html


External links

Nomenclature
HGNC (Hugo)RASSF6 &n"sp;&Nbsq;20796
Cards
AtlasRASSF6ID43462ch4q13
Entrez_Gene (NCBI)RASSF6  166824  Ras association domain family member 6
Aliases
GeneCards (Weizmann)RASSF6
Ensembl hg19 (Hinxton)ENSG00000169435<a> [Wee_View]
Ensembl hg38 (Hinxton)ENSG00000169435 [Gene_View]  chr4:73571550-73620570 [Contig_View]  RASSF6 [Vega]
ICGC DataPortalENSG00000169435
TCGA cBioPortalRASSF6
AceView (NCBI)RASSF6
Genatlas (Paris)RASSF6
WikiGenes166824
SOURCE (Princeton)RASSF6
Genetics Home Reference (NIH)RASSF6
Genomic and cartography
GoldenPath hg38 (UCSC)RASSF6  -     chr4:73571550-73620570 -  4q13.3   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)RASSF6  -     4q13.3   [Description]    (hg19-Feb_2009)
EnsemblRASSF6 - 4q13.3 [CytoView hg19]  RASSF6 - 4q13.3 [CytoView hg38]
Mapping of homologs : NCBIRASSF6 [Mapview hg19]  RASSF6 [Mapview hg38]
OMIM612620   
Gene and transcription
Genbank (Entrez)AI579909 AK002032 AK126346 AW070877 AW407403
RefSeq transcript (Entrez)NM_001270391 NM_001270392 NM_177532 NM_201431
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)RASSF6
Cluster EST : UnigeneHs.529677 [ NCBI ]
CGAP (NCI)Hs.529677
Alternative Splicing GalleryENSG00000169435
Gene ExpressionRASSF6 [ NCBI-GEO ]   RASSF6 [ EBI - ARRAY_EXPRESS ]   RASSF6 [ SEEK ]   RASSF6 [ MEM ]
Gene Expression Viewer (FireBrowse)RASSF6 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)166824
GTEX Portal (Tissue expression)RASSF6
Human Protein AtlasENSG00000169435-RASSF6 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ6ZTQ3   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ6ZTQ3  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ6ZTQ3
Splice isoforms : SwissVarQ6ZTQ3
PhosPhoSitePlusQ6ZTQ3
Domaine pattern : Prosite (Expaxy)RA (PS50200)    SARAH (PS50951)   
Domains : Interpro (EBI)C-RASSF    RA_dom    RASSF6    SARAH_dom    Ubiquitin-rel_dom   
Domain families : Pfam (Sanger)Nore1-SARAH (PF16517)    RA (PF00788)   
Domain families : Pfam (NCBI)pfam16517    pfam00788   
Domain families : Smart (EMBL)RA (SM00314)  
Conserved Domain (NCBI)RASSF6
DMDM Disease mutations166824
Blocks (Seattle)RASSF6
SuperfamilyQ6ZTQ3
Human Protein Atlas [tissue]ENSG00000169435-RASSF6 [tissue]
Peptide AtlasQ6ZTQ3
HPRD15220
IPIIPI00398796   IPI00176707   IPI00384451   IPI00760776   
Protein Interaction databases
DIP (DOE-UCLA)Q6ZTQ3
IntAct (EBI)Q6ZTQ3
FunCoupENSG00000169435
BioGRIDRASSF6
STRING (EMBL)RASSF6
ZODIACRASSF6
Ontologies - Pathways
QuickGOQ6ZTQ3
Ontology : AmiGOprotein binding  apoptotic process  signal transduction  regulation of apoptotic process  
Ontology : EGO-EBIprotein binding  apoptotic process  signal transduction  regulation of apoptotic process  
Pathways : KEGGHippo signaling pathway   
NDEx NetworkRASSF6
Atlas of Cancer Signalling NetworkRASSF6
Wikipedia pathwaysRASSF6
Orthology - Evolution
OrthoDB166824
GeneTree (enSembl)ENSG00000169435
Phylogenetic Trees/Animal Genes : TreeFamRASSF6
HOVERGENQ6ZTQ3
HOGENOMQ6ZTQ3
Homologs : HomoloGeneRASSF6
Homology/Alignments : Family Browser (UCSC)RASSF6
Gene fusions - Rearrangements
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerRASSF6 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)RASSF6
dbVarRASSF6
ClinVarRASSF6
1000_GenomesRASSF6 
Exome Variant ServerRASSF6
ExAC (Exome Aggregation Consortium)ENSG00000169435
GNOMAD BrowserENSG000p016935=/a>
Genetic variants : HAPMAP166824
Genomic Variants (DGV)RASSF6 [DGVbeta]
DECIPHERRASSF6 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisRASSF6 
Mutations
ICGC Data PortalRASSF6 
TCGA Data PortalRASSF6 
Broad Tumor PortalRASSF6
OASIS PortalRASSF6 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICRASSF6  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDRASSF6
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch RASSF6
DgiDB (Drug Gene Interaction Database)RASSF6
DoCM (Curated mutations)RASSF6 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)RASSF6 (select a term)
intoGenRASSF6
NCG5 (London)RASSF6
Cancer3DRASSF6(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM612620   
Orphanet
MedgenRASSF6
Genetic Testing Registry RASSF6
NextProtQ6ZTQ3 [Medical]
TSGene166824
GENETestsRASSF6
Target ValidationRASSF6
Huge Navigator RASSF6 [HugePedia]
snp3D : Map Gene to Disease166824
BioCentury BCIQRASSF6
ClinGenRASSF6
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD166824
Chemical/Pharm GKB GenePA134900075
Clinical trialRASSF6
Miscellaneous
canSAR (ICR)RASSF6 (select the gene name)
Probes
Litterature
PubMed23 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineRASSF6
EVEXRASSF6
GoPubMedRASSF6
iHOPRASSF6
REVIEW articlesautomatic search in PubMed
Last year publication{8/A>automatic search in PubMed

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