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RASSF2 (Ras association (RalGDS/AF-6) domain family member 2)

Written2009-08Luke 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 : )

Identity

Alias_namesRas association (RalGDS/AF-6) domain family member 2
Alias_symbol (synonym)KIAA0168
CENP-34
Other aliasDKFZp781O1747
RASFADIN
HGNC (Hugo) RASSF2
LocusID (NCBI) 9770
Atlas_Id 43461
Location 20p13  [Link to chromosome band 20p13]
Location_base_pair Starts at 4780024 and ends at 4823645 bp from pter ( according to hg19-Feb_2009)  [Mapping RASSF2.png]
Local_order Telomere-PRNP-PRNT-RASSF2-SLC23A2-Centromere.
Juxtaposed to the PRNP prion locus conserved in the syntenic bovine region (Choi et al., 2006).
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
HLA-DPB1 (6p21.32) / RASSF2 (20p13)RASSF2 (20p13) / FGR (1p36.11)
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 inactivation of RASSF2 has been described in a growing number of tumour types. RASSF2 functions as a K-Ras adaptor protein and mediates some of the growth inhibitory properties of K-Ras. RASSF2 regulates apoptosis and cell cycle progression through interactions with several downstream effectors including MST1 and MST2.

DNA/RNA

 
  Figure 1: RASSF2 gene structure. Transcription of the RASSF2A isoforms begins within a CpG island that spans exons 1 and 2 (grey box) at -105 to +1745 bp relative to the transcription start site of NM_014737. RASSF2B transcription begins at exon 1beta in intron 5. Transcription of RASSF2C begins at exon 1gamma in intron 2. RASSF2B and RASSF2C do not have 5' CpG islands or predicted promoter regions.
Description The RASSF2 gene occupies 43,621bp of genomic DNA (-ve strand). RASSF2A variant 1 [GenBank:NM_014737] contains 12 exons and is transcribed from a large (1,850bp) 5' CpG island encompassing the first two non-coding exons. There is evidence of multiple splice variants and transcription initiation sites for the RASSF2 gene. Additional isoforms of RASSF2 include RASSF2A variant 2 [GenBank:CR627436] that is predicted to produce an identical protein to RASSF2A variant 1, RASSF2B [GenBank:AY154471] and RASSF2C [GenBank:AY154472]. A further isoform [GenBank:CR620887] produces a non-coding mRNA. RASSF2B and RASSF2C are not associated with CpG islands (figure 1). Akino et al., (2005) investigated promoter activity of the region upstream of the transcription start site of NM_014737 (RASSF2A variant 1) and found promoter activity was dependent on a CACCC box and SP1 site just upstream of exon 1. The authors however did not investigate the CpG island region of the RASSF2 gene, which is largely located in intron 1 of the NM_014737 transcript.

Protein

 
  Figure 2: RASSF2 transcript and protein structure. RASSF2A [GenBank:NP_055552] is a 326 aa protein containing a central bipartite nuclear localisation signal (NLS), a Ras-association (RA) domain of the RalGDS/AF-6 variety and acidic coiled-coil Sav/RASSF/Hpo (SARAH) domain. RASSF2B [GenBank:AAN59976] is a predicted 157 amino acid protein containing a truncated RA domain. The RASSF2C predicted protein is identical to RASSF2A. The mRNA transcript shown (red bar) represents RASSF2A variant 1 (NM_014737).
Description As mentioned above multiple isoforms are expressed from the RASSF2 locus. However, RASSF2A variants 1 and 2, as well as RASSF2C (if expressed at all) contain identical open reading frames encoding a 326 amino acid protein, whilst RASSF2B mRNA is predicted to encode a truncated protein of 157 amino acids but is expressed at extremely low levels in all tissues analysed. Therefore, the protein is simply referred to as RASSF2 in the literature. The RASSF2 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). In addition RASSF2 contains a central bipartite nuclear localisation signal (NLS) which has been shown to be essential for tumour suppressor function (Cooper et al., 2008). The C-terminus of RASSF2 also contains a sequence shown to be necessary for nuclear export (Kumari et al., 2009). Detection of endogenous RASSF2 protein has been described in a variety of cell lines using an in-house antibody (Vos et al., 2003) or a commercially available antibody from Santa Cruz (Cooper et al., 2009).
 
  Figure 3: RASSF2 is conserved with RASSF paralogues. Schematic representation of the 10 human members of the RASSF family showing the Ras-association, SARAH and predicted diacylglycerol binding domains. The longest isoform for each RASSF gene is represented (GenBank accession numbers: RASSF1A[NP_009113], RASSF2[NP_055552], RASSF3[NP_835463], RASSF4[NP_114412], RASSF5A[NP_872604], RASSF6[NP_958834], RASSF7[NP_003466], RASSF8[BAC98838], RASSF9[NP_005438], RASSF10[NP_001073990]). The RASSF family is subdivided into 'classical' RASSF members and 'N-terminal' RASSF members as indicated. Shown is the percentage amino acid identity of each RASSF members with RASSF2. Protein sequence identity of the 'classical' RASSF members is greatest over the C-terminus. * RASSF10 protein sequence as described in Hesson et al., 2009 (which is N-terminally truncated with respect to GenBank accession number NP_001073990).
Expression Northern blotting shows RASSF2 mRNA is highly expressed in many normal tissues including brain, thymus, spleen, liver, small intestines, placenta, lung and peripheral blood (Vos et al., 2003). The probe used for northern blotting did not discriminate between RASSF2 isoforms. The coding region of RASSF2 has been cloned from a brain-specific cDNA library (Hesson et al., 2005). Currently there has been limited analysis of expression patterns and distribution of the different RASSF2 isoforms. RASSF2A variants 1 and 2 are both ubiquitously expressed in a range of normal tissues including colon, stomach, heart, bone marrow, kidney, ovary, lung, liver, breast, testis and pancreas (Maruyama et al., 2008). However, expression of the RASSF2B and RASSF2C isoforms was virtually undetectable in a range of normal tissues (Maruyama et al., 2008; L Hesson and F Latif, unpublished observations). Expression of the RASSF2 gene is inactivated by DNA methylation of the 5' CpG island promoter region in a broad spectrum of cancers (see below).
Localisation When over expressed RASSF2 is clearly predominantly nuclear, as demonstrated by immunofluorescence (Cooper et al., 2008; Kurnari et al., 2007). Some evidence suggests that the NLS of RASSF2 is an integral part of the ability of RASSF2 to act as a tumour suppressor. The localisation of RASSF2 is cell context specific. Two independent studies indicate that phosphorylation of RASSF2 appears to be critical for relocalisation to the cytoplasm, though the critical phosphorylation sites remain to be determined. Cooper et al., (2009) demonstrated that relocalisation of over expressed RASSF2 from the nucleus to the cytoplasm is dependent on active MST1 or MST2 and that either kinase was capable of phosphorylating RASSF2 in vitro. However, the work of Kumari et al., (2009) demonstrates that RASSF2 relocalisation is dependent on the activity of Extracellular signal-Related Kinase 2 (ERK2). Both MSTs and ERK2 can participate in Ras signalling therefore both studies may be observing the effects of activation of the same pathway. The presence of sequences essential for both nuclear import and export within RASSF2 seems to suggest that the protein may continuously cycle between cytoplasm and nucleus in a similar manner to MST1 and MST2 (Lee and Yonehara, 2002). Given the strong binding of RASSF2 with MST1 and MST2 (see below) it seems likely that this would occur in complex with MSTs. RASSF2 nuclear important may be dependent on importin-alpha interaction (Kumari et al., 2007), whilst nuclear export appears to involve the NES (nuclear export signal)-dependent transport protein CRM-1/XPO1 (Kumari et al., 2009). What remains to be determined is the exact conditions under which the kinetics of nuclear export predominates nuclear import and vice versa.
Function Tumour suppressor function of RASSF2
Similar to several other RASSF members RASSF2 suppresses tumour growth when expressed. This has been demonstrated for colorectal, lung, breast, gastric, nasopharyngeal and oral squamous cell carcinoma (OSCC) cell lines in vitro using colony formation, growth curve and soft agar growth assays (Akino et al., 2005; Vos et al., 2003; Cooper et al., 2008; Maruyama et al., 2008; Imai et al., 2008; Zhang et al., 2006). Furthermore, RASSF2 re-expression in breast tumour cells inhibits in vivo tumour growth when cells are subcutaneously injected into severe combined immunodeficiency (SCID) mice (Cooper et al., 2008). Several studies demonstrate that these tumour suppressive properties are likely to arise from the ability of RASSF2 to regulate apoptosis and cell cycle progression (Vos et al., 2003; Maruyama et al., 2008; Imai et al., 2008; Akino et al., 2005). In breast cancer cells and Cos-7 cells growth suppression by RASSF2 is dependent on the nuclear localisation signal (NLS) located at amino acids 151-167 (Cooper et al., 2008; Kumari et al., 2009), whilst other reports have indicated that in OSCC and gastric cancer cells the C-terminal portion of RASSF2 (RASSF2 [163-326]), containing the RA domain, is critical for tumour suppressive function (Imai et al., 2008; Maruyama et al., 2008). Interestingly, in OSCC this C-terminal portion exhibited enhanced growth suppression relative to full length RASSF2 (Imai et al., 2008). In fact, RASSF2 [163-326] also disrupts the NLS yet leaves the sequence required for nuclear export intact. In a separate study of colorectal cancer cells both RASSF2 truncations (RASSF2 [1-163] and RASSF2 [163-326]) exhibited reduced growth suppression compared to full length RASSF2 (Akino et al., 2005). Whilst in gastric cancer transfection of RASSF2 with deletion of the NLS [RASSF2deltaNLS] actually increased the percentage of apoptotic cells relative to full length RASSF2 (Maruyama et al., 2008). These studies indicate the growth suppressive properties of RASSF2 are likely cell background specific but more importantly that nuclear import, nuclear export and the Ras-association domain are required for correctly regulated RASSF2 growth suppression.

RASSF2 interaction with Ras
RASSF2 contains a functional RA domain that displays a strong binding to K-Ras, but only weak binding to H-Ras (Vos et al., 2003). RASSF2 associates with the K-Ras effector domain in a GTP-dependent manner thus displaying the basic properties of a genuine Ras effector. RASSF2 growth inhibition is enhanced in the presence of K-RasG12V. Furthermore, siRNA-mediated knock-down of RASSF2 in K-Ras transformed cells enhanced anchorage-independent growth. However, in the absence of K-Ras transformation knock-down of RASSF2 inhibited growth (Akino et al., 2005). These data indicate that RASSF2 mediates some of the growth inhibitory properties of K-Ras and that inactivation of RASSF2 enhances K-Ras-induced transformation.

RASSF2 interaction with the proapoptotic kinases MST1 and MST2
How the interaction of RASSF proteins with Ras results in growth suppression has been the subject of intense investigation. The proapoptotic mammalian Serine/Threonine kinases MST1 and MST2 were identified as RASSF2 interacting partners by yeast two-hybrid (Y2-H) (Khokhlatchev et al., 2002). RASSF1 and RASSF5 were also identified as MST binding partners as part of a novel Ras-regulated signalling pathway. Recently the interaction of RASSF2 and MST1/2 was formally demonstrated in human cells at the endogenous level. Interaction occurs between the SARAH domains found within RASSF2 and MST1/2 (Cooper et al., 2009). RASSF2 appears to have a distinct role in regulating MST2 function. Activation of MST2 is followed by a rapid proteasome-dependent loss of MST2 stability (that is not associated with MST2 cleavage). Interestingly, over expression of RASSF2 results in increased levels of MST2 and provides protection of MST2 from degradation following its activation. In agreement with this loss on RASWF protein in colorectal tumours, or in colorectal tumour cell lines in which RASSF2 levels are decreased by shRNAi, also leads to decreases in MST2 levels (Cooper et al., 2009). RASSF2 appears to be a substrate for MST1 and MST2 and co-expression of either kinase with RASSF2 relocalises RASSF2 from the nucleus to the cytoplasm in a manner dependent on kinase activity (Cooper et al., 2009). Since MST2 remains in complex with RASSF2 following its activation these data collectively suggest RASSF2 stabilises active MST2 allowing (or perhaps even targeting) MST2 substrate phosphorylation. This RASSF2-mediated stabilisation also appears to be true for MST1. Thus loss of RASSF2, as is frequently observed in cancer, leads to loss of MST1 and MST2 leading to a decrease in apoptotic potential. That RASSF2 appears to be capable of influencing MST stability so drastically is likely to be due to the observation that the majority of both MST1 and MST2 are in complex with RASSF2 in at least some cell types (Cooper et al., 2009). The interaction of RASSF2 with MST1/2 poses an interesting question with regards to the regulation of RASSF2 localisation. Both RASSF2 and MST1/2 have been shown to contain sequences essential for nuclear import and export (Lee and Yonehara, 2002; Kumari et al., 2009). Both the NLS and NES sequences within MST1/2 and RASSF2 respectively are located very close to or within the SARAH domains and neither are canonical NLS/NES sequences. Mapping of both these sequences were determined by deletion mapping, which would most likely also affect RASSF2-MST1/2 interaction thus it now seems likely that the RASSF2-MST1/2 complex constantly cycles between the nucleus (by virtue of RASSF2 NLS) and cytoplasm (by virture of MST1/2 NES) and disruption of the interaction between RASSF2 and MST1/2 would likely affect the localisation of both proteins. Also, the fact that RASSF2 translocation to the cytoplasm is dependent on ERK2 activity (Kumari and Mahalingam, 2009) suggests the Ras-MEK-ERK pathway may serve to phosphorylate MST1/2, which then phosphorylates RASSF2, translocating it to the cytoplasm and allowing RASSF2 to interact with Ras (figure 4). That nuclear RASSF2 is required for full tumour suppressor activity (Cooper et al., 2008; Kumari et al., 2009) may be explained by the fact that ERK2 translocates to the nucleus upon its activation (Khokhlatchev et al., 1998).

Other functions of RASSF2
Other functions and interacting partners of RASSF2 are extremely likely. Y2-H using RASSF2 as bait implicates NORE1A and RASSF3 in RASSF2 function, although these have not yet been confirmed in mammalian cells (Hesson et al., 2005). These interactions may implicate other RASSF members in modulating RASSF2 function and suggests a complex network of cross-talk between signalling pathways involving RASSF proteins. Also, the exact mechanisms of apoptotic and cell cycle regulation of RASSF2 have yet to be completely defined. Microarray analysis of gene expression before and after exogenous expression of RASSF2 in gastric and OSCC cancer cell lines showed RASSF2 downregulates expression of several inflammatory response genes including the cytokines IL-8, LCN2, CXCL1, CXCL2, CXCL3, CXCL5 and CXCL6, CCL20 and CCL21 and genes involved in immune-cell chemotaxis (Maruyama et al., 2008; Imai et al., 2008). A possible pathway influenced by RASSF2 is the NF-kB pathway since over expression of RASSF2 significantly downregulated NF-kB transcriptional activity (Maruyama et al., 2008; Imai et al., 2008). Of note is the recent observation that pigs experimentally infected with Porcine Circovirus Type 2 (PCV2) show upregulation of several CXCL family cytokines as well as RASSF2 (Fernandes et al., 2009) therefore it is likely a role for RASSF2 in regulating immune response pathways remains to be discovered. There is also evidence that RASSF2 may regulate the actin cytoskeleton since re-expression of RASSF2 leads to loss of stress fibres, cell rounding and the suppression of RhoGTPase activation (Maruyama et al., 2008; Akino et al., 2005). Additionally, RASSF2 upregulation appears to be a cellular response to ionising radiation (Sakamoto-Hojo et al., 2003).

 
  Figure 4: One possible RASSF2 pathway. Recent evidence suggests a RASSF2-MST1/2 complex may continuously cycle through the nucleus and that nuclear localisation of RASSF2 is essential for tumour suppressor function. There are also reports demonstrating that the activity of the kinases ERK2 and MST1/2 is crucial for cytoplasmic relocalisation of RASSF2. Therefore activation of the RASSF2 tumour suppressor pathway may emanate from the nucleus following ERK2 and MST1/2 activation allowing RASSF2 to accumulate in the cytoplasm where it may encounter another interacting partner K-RasGTP.
Homology Human RASSF2 has highly conserved orthologues across many species (table 1). The main features of the RASSF2 protein are conserved across these species including the RA and SARAH domains as well as the NLS and the sequence important for nuclear export. RASSF2 is one of 10 members of the Ras-association domain family (RASSF) comprising RASSF1-10. 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. RASSF7-10 (RASSF7, RASSF8, RASSF9, 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. RASSF2 is most similar to RASSF4 and RASSF6 (figure 3), both of which are also epigenetically inactivated in cancer, and participate in K-Ras signalling to inhibit tumour cell growth and induce apoptosis (Hesson et al., 2009; Ikeda et al., 2006; Allen et al., 2006; Eckfeld et al., 2005; Chow et al., 2004).
 

Mutations

Note Similar to all other RASSF members, perhaps with the exception of RASSF1A (Kashuba et al., 2009; Pan et al., 2005), mutation of RASSF2 is a rare event and to date no inactivating mutations have been described. Analysis of ovarian primary tumours failed to identify a single amino acid changing or truncating point mutation (Cooper et al., 2008). However, more thorough investigations of larger cohorts of different tumour types may be required to determine this definitively.

Implicated in

Note
  
Entity Colorectal carcinoma (CRC)
Note Colorectal carcinoma (CRC) including colon adenomas.
Prognosis In early colorectal cancers RASSF2 methylation with oncogenic activation of either K-Ras, B-Raf or PIK3CA presented significantly more frequently in cases of venous invasion (Nosho et al., 2007).
Oncogenesis Similar to several other RASSF members, RASSF2 is frequently inactivated by CpG island DNA hypermethylation (Hesson et al., 2007). RASSF2 inactivation has been most extensively investigated in colorectal cancer in which inactivation of other RASSF members is relatively rare. Several studies now strongly suggest that RASSF2 inactivation is a frequent and early event in colorectal cancer formation being present in colon adenomas, particularly those with a villous component (Kakar et al., 2008; Hesson et al., 2005; Akino et al., 2005; Harada et al., 2007). The frequencies of RASSF2 methylation in CRCs vary between 42% (Akino et al., 2005) and 70% (Hesson et al., 2005) whilst for adenomas methylation occurs between 25% (Harada et al., 2007) and 94% (Kakar et al., 2008). This most likely reflects the differences in histopathological subtypes and the CpG island region analysed as well differences in colorectal cancer aetiology in different populations. Some reports describe variable frequencies of RASSF2 methylation depending on tumour location within the colon (Harada et al., 2007). Interestingly, cells from apparently normal colonic epithelium from patients with hyperplastic polyposis (HPP) also frequently demonstrate methylation of several TSGs including RASSF2 (Minoo et al., 2006). This may indicate an early role for RASSF2 inactivation in colonic hyperplasia. RASSF2 methylation was found to be associated with K-Ras or BRAF mutation (Harada et al., 2007; Akino et al., 2005) however, in another study K-Ras mutation and RASSF2 methylation were mutually exclusive (Hesson et al., 2005). Methylation of the RASSF2 promoter and loss of expression occurred in conjunction with loss of histone H3 acetylation, a marker of transcriptional activity. Reduced RASSF2A expression also correlated with methylation in primary CRCs (Akino et al., 2005). In colorectal tumour cell lines re-expression of RASSF2 resulted in inhibition of anchorage-independent growth in soft agar, which was associated with morphological changes, cell detachment, disruption of the actin stress fibre network, decreased Rho activity, increased apoptosis and inhibition of cell cycle progression. Deregulation of the actin cytoskeletal network and morphological changes that result in cellular detachment may therefore be a mechanism by which RASSF2 induces anoikis, a form of suspension-dependent apoptosis.
  
  
Entity Non-small cell lung carcinoma (NSCLC)
Oncogenesis Investigation of NSCLC primary tumours found methylation of the RASSF2 CpG island in 44% (22/50). Methylation was found at an equal frequency in all grades (I/II = 44% (7/16); IIIA = 44% (4/9) and IV = 44% (10/23)) suggesting RASSF2 became hypermethylated early in tumour formation and was not associated with development to higher grades (Cooper et al., 2008). The incidence of RASSF2 methylation appears much more frequent in NSCLC than SCLC (small cell lung cancer) as shown by an earlier study by Kaira et al., (2007), in which only 18% (4/22) SCLC but 62% (16/26) NSCLC cell lines demonstrated RASSF2 methylation with concomitant loss of RASSF2A expression. RASSF2A expression was restored following treatment with the DNA demethylating agent 5-aza-2'deoxycytidine and/or trichostatin A. In primary NSCLC tumours 31% (33/106) were methylated and methylation was more frequent in specimens from non-smokers than from smokers (45%, 18/40 vs 23%, 15/66 respectively; p=0.014).
  
  
Entity Nasopharyngeal carcinoma
Prognosis RASSF2 methylation correlated with lymph node metastasis in nasopharyngeal carcinoma (Zhang et al., 2006).
Oncogenesis Fifty one percent (27/53) of primary nasopharyngeal carcinomas (NPCs) showed cancer-specific RASSF2 methylation, which correlated with loss of RASSF2A expression in both NPC cell lines and primary tumours (Zhang et al., 2006). This study also provided evidence that RASSF2 re-expression suppressed colony formation ability in NPC cell lines (with concomitant inhibition of cell cycle progression) and decreased cell motility and migration as determined by wound healing assay.
  
  
Entity Gastric cancer
Prognosis Both Maruyama et al., (2008) and Endoh et al., (2005) found DNA methylation of the region around the transcription start site of RASSF2A variant 1 significantly correlated with an absence of lymphatic invasion. Whilst Maruyama et al., (2009) found further associations with methylation and the absence of venous invasion or lymph node metastasis, less advanced stage, presence of EBV infection, the absence of TP53 mutations and the presence of a CpG-island methylator phenotype (CIMP).
Oncogenesis The RASSF2 gene contains a 1.8kb CpG island that encompasses the first two non-coding exons (figure 1). The majority of this CpG island was interrogated for hypermethylation in a series of gastric cancers (Endoh et al., 2005). The study found varying frequencies of methylation throughout the CpG island ranging from 29% (23/78) at the region encompassing the transcription start site, to 79% (62/78) at a region of the CpG island within intron 1 (though this intronic region also exhibited a frequency of 60% (47/78) methylation in corresponding normal gastric epithelia). Methylation was mostly cancer specific at and around the transcription start site and silencing of RASSF2A expression most closely correlated with methylation at this region (Endoh et al., 2005). Similar findings were described by Maruyama et al., (2008) who examined the methylation status of the CpG island regions encompassing the transcriptional start sites of RASSF2A variants 1 and 2. Methylation of RASSF2A variant 1 was detected in 29.5% (23/78), whilst RASSF2A variant 2 was methylated in 25.6% (23/78) of gastric cancer cases. This may be significant since the expression of RASSF2A variants 1 and 2 appear to be differentially regulated by DNA methylation from within the same CpG island indicating multiple promoters and possibly accounting for the differences in methylation densities throughout the region. RASSF2A re-expression inhibited the growth of gastric cancer cell lines as shown by reduced colony formation ability. This was a result of inhibition of cell cycle progression and induction of apoptosis (Maruyama et al., 2008).
  
  
Entity Prostate cancer
Prognosis A prospective study of a large cohort of patients referred for prostate biopsy determined that detection of RASSF2 methylation in patient urine shows promising clinical utility as an early detection biomarker for prostate cancer (Payne et al., 2009). Though primary prostate tumour tissues were not investigated the study nevertheless provided information independent of the extensively used pre-existing prostate cancer biomarker PSA (prostate specific antigen). Detection of RASSF2 methylation was significantly more frequent in patients with non-organ-confined prostate cancer (Payne et al., 2009). Thus RASSF2 methylation may represent an interesting biomarker for early prostate cancer detection and predicting invasive potential but requires further validation.
  
  
Entity Breast cancer
Oncogenesis RASSF2 was frequently hypermethylated in primary breast cancers (38%, 15/40) and re-expression in breast cancer cell lines inhibited colony formation ability, anchorage-independent growth in soft agar and in vivo tumour formation in SCID mice (Cooper et al., 2008). RASSF2 growth suppression was dependent on a functional NLS (located at amino acids 151-167) since its mutation prevented anchorage-independent growth inhibition.
  
  
Entity Hepatocellular carcinoma (HCC)
Oncogenesis In an extensive DNA hypermethylation analysis of cancerous and non-cancerous liver tissues (including normal liver tissues from non-cancer patients) Nishida et al., (2008) assessed the methylation status of 19 gene loci in hepatitis B virus (HBV) and hepatitis C virus (HCV)-related HCCs. This study found that normal ageing within liver tissues is associated with a gradual increase in aberrant methylation and that HCV infection in particular may accelerate age-related methylation. RASSF2 methylation was identified as a cancer-specific event that is completely absent in normal liver (0/22), infrequent in non-cancerous liver from HCC patients (2.6%, 2/77), yet frequent in HCV-related HCC (48%, 21/44) vs virus-negative HCC (5.6%, 1/18; p=0.0029). Though this suggests loss of RASSF2 expression may play a role in HCC the potential importance and clinical implications of these findings require further investigation.
  
  
Entity Oral squamous cell carcinoma (OSCC)
Oncogenesis Analysis of the expression of RASSF1-6 in OSCC cell lines identified RASSF2 as the most frequently downregulated RASSF gene analysed. This loss of expression was caused by RASSF2 CpG island methylation, which was found in 26% (12/46) of primary OSCCs (Imai et al., 2008). In OSCC cell lines re-expression of RASSF2 inhibited colony formation ability by inducing apoptosis and inhibiting cell cycle progression. Investigation of 482 OSCCs identified RASSF2 methylation in 28% (134/482) cases. The combination of RASSF1A and RASSF2 methylation was significantly associated with poor disease-free survival (p=0.009, Huang et al., 2009). Furthermore, methylation of RASSF1A and RASSF2 increased in patients undergoing post-surgical radiotherapy when compared with surgery-only patients possibly indicating that hypermethylation of RASSF1A and RASSF2 is associated with the radioresistance commonly observed in OSCC patients. It also indicates the potential of using combined epigenetic and radiotherapy as an adjuvant to surgery.
  
  
Entity Endometrial carcinoma
Oncogenesis Liao et al., (2008) investigated endometrial carcinomas for RASSF2 CpG island methylation and found 25/76 (33%) were methylated. RASSF2 methylation was found more frequently in tumour samples from older patients. Similar findings were observed in colorectal carcinomas (Hesson et al., 2005) and in OSCC (Imai et al., 2008) suggesting loss of RASSF2 expression may be a gradual age-related process.
  
  
Entity Ovarian cancer
Oncogenesis Although methylation of the RASSF2 promoter is not an event associated with ovarian cancer (Cooper et al., 2008) the gene does localise to one of the regions deleted in ovarian tumour cell lines as indicated by array-based genomic hybridisation (Lambros et al., 2005).
  
  
Entity Leukaemia
Oncogenesis Recent evidence suggests that RASSF2 expression may be downregulated in leukaemias with MLL rearrangement by overexpression of one or more of the miR-17-92 polycistronic miRNA oncogene cluster (Li et al., 2009) that may target a region within the 3'UTR of the RASSF2 mRNA.
  

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Fernandes LT, Tomas A, Bensaid A, Perez-Enciso M, Sibila M, Sanchez A, Segales J.
Anim Biotechnol. 2009;20(3):96-109.
PMID 19544206
 
Genetic and epigenetic alterations of Ras signalling pathway in colorectal neoplasia: analysis based on tumour clinicopathological features.
Harada K, Hiraoka S, Kato J, Horii J, Fujita H, Sakaguchi K, Shiratori Y.
Br J Cancer. 2007 Nov 19;97(10):1425-31. Epub 2007 Oct 9.
PMID 17923875
 
The role of RASSF1A methylation in cancer.
Hesson LB, Cooper WN, Latif F.
Dis Markers. 2007;23(1-2):73-87. (REVIEW)
PMID 17325427
 
The novel RASSF6 and RASSF10 candidate tumour suppressor genes are frequently epigenetically inactivated in childhood leukaemias.
Hesson LB, Dunwell TL, Cooper WN, Catchpoole D, Brini AT, Chiaramonte R, Griffiths M, Chalmers AD, Maher ER, Latif F.
Mol Cancer. 2009 Jul 1;8:42.
PMID 19570220
 
CpG island promoter hypermethylation of a novel Ras-effector gene RASSF2A is an early event in colon carcinogenesis and correlates inversely with K-ras mutations.
Hesson LB, Wilson R, Morton D, Adams C, Walker M, Maher ER, Latif F.
Oncogene. 2005 Jun 2;24(24):3987-94.
PMID 15806169
 
Methylation of RASSF1A, RASSF2A, and HIN-1 is associated with poor outcome after radiotherapy, but not surgery, in oral squamous cell carcinoma.
Huang KH, Huang SF, Chen IH, Liao CT, Wang HM, Hsieh LL.
Clin Cancer Res. 2009 Jun 15;15(12):4174-80. Epub 2009 Jun 9.
PMID 19509163
 
Ras-association domain family protein 6 induces apoptosis via both caspase-dependent and caspase-independent pathways.
Ikeda M, Hirabayashi S, Fujiwara N, Mori H, Kawata A, Iida J, Bao Y, Sato Y, Iida T, Sugimura H, Hata Y.
Exp Cell Res. 2007 Apr 15;313(7):1484-95. Epub 2007 Feb 23.
PMID 17367779
 
Epigenetic inactivation of RASSF2 in oral squamous cell carcinoma.
Imai T, Toyota M, Suzuki H, Akino K, Ogi K, Sogabe Y, Kashima L, Maruyama R, Nojima M, Mita H, Sasaki Y, Itoh F, Imai K, Shinomura Y, Hiratsuka H, Tokino T.
Cancer Sci. 2008 May;99(5):958-66. Epub 2008 Feb 24.
PMID 18294275
 
Epigenetic inactivation of the RAS-effector gene RASSF2 in lung cancers.
Kaira K, Sunaga N, Tomizawa Y, Yanagitani N, Ishizuka T, Saito R, Nakajima T, Mori M.
Int J Oncol. 2007 Jul;31(1):169-73.
PMID 17549418
 
CpG island methylation is frequently present in tubulovillous and villous adenomas and correlates with size, site, and villous component.
Kakar S, Deng G, Cun L, Sahai V, Kim YS.
Hum Pathol. 2008 Jan;39(1):30-6. Epub 2007 Oct 24.
PMID 17950780
 
High mutability of the tumor suppressor genes RASSF1 and RBSP3 (CTDSPL) in cancer.
Kashuba VI, Pavlova TV, Grigorieva EV, Kutsenko A, Yenamandra SP, Li J, Wang F, Protopopov AI, Zabarovska VI, Senchenko V, Haraldson K, Eshchenko T, Kobliakova J, Vorontsova O, Kuzmin I, Braga E, Blinov VM, Kisselev LL, Zeng YX, Ernberg I, Lerman MI, Klein G, Zabarovsky ER.
PLoS One. 2009 May 29;4(5):e5231.
PMID 19478941
 
Identification of a novel Ras-regulated proapoptotic pathway.
Khokhlatchev A, Rabizadeh S, Xavier R, Nedwidek M, Chen T, Zhang XF, Seed B, Avruch J.
Curr Biol. 2002 Feb 19;12(4):253-65.
PMID 11864565
 
Extracellular signal-regulated kinase 2 (ERK-2) mediated phosphorylation regulates nucleo-cytoplasmic shuttling and cell growth control of Ras-associated tumor suppressor protein, RASSF2.
Kumari G, Mahalingam S.
Exp Cell Res. 2009 Oct 1;315(16):2775-90. Epub 2009 Jun 23.
PMID 19555684
 
Nuclear transport of Ras-associated tumor suppressor proteins: different transport receptor binding specificities for arginine-rich nuclear targeting signals.
Kumari G, Singhal PK, Rao MR, Mahalingam S.
J Mol Biol. 2007 Apr 13;367(5):1294-311. Epub 2007 Jan 12.
PMID 17320110
 
Analysis of ovarian cancer cell lines using array-based comparative genomic hybridization.
Lambros MB, Fiegler H, Jones A, Gorman P, Roylance RR, Carter NP, Tomlinson IP.
J Pathol. 2005 Jan;205(1):29-40.
PMID 15586366
 
Phosphorylation and dimerization regulate nucleocytoplasmic shuttling of mammalian STE20-like kinase (MST).
Lee KK, Yonehara S.
J Biol Chem. 2002 Apr 5;277(14):12351-8. Epub 2002 Jan 22.
PMID 11805089
 
Consistent deregulation of gene expression between human and murine MLL rearrangement leukemias.
Li Z, Luo RT, Mi S, Sun M, Chen P, Bao J, Neilly MB, Jayathilaka N, Johnson DS, Wang L, Lavau C, Zhang Y, Tseng C, Zhang X, Wang J, Yu J, Yang H, Wang SM, Rowley JD, Chen J, Thirman MJ.
Cancer Res. 2009 Feb 1;69(3):1109-16. Epub 2009 Jan 20.
PMID 19155294
 
Hypermethylation of RAS effector related genes and DNA methyltransferase 1 expression in endometrial carcinogenesis.
Liao X, Siu MK, Chan KY, Wong ES, Ngan HY, Chan QK, Li AS, Khoo US, Cheung AN.
Int J Cancer. 2008 Jul 15;123(2):296-302.
PMID 18404674
 
Cytoplasmic RASSF2A is a proapoptotic mediator whose expression is epigenetically silenced in gastric cancer.
Maruyama R, Akino K, Toyota M, Suzuki H, Imai T, Ohe-Toyota M, Yamamoto E, Nojima M, Fujikane T, Sasaki Y, Yamashita T, Watanabe Y, Hiratsuka H, Hirata K, Itoh F, Imai K, Shinomura Y, Tokino T.
Carcinogenesis. 2008 Jul;29(7):1312-8. Epub 2008 Feb 29.
PMID 18310659
 
Extensive DNA methylation in normal colorectal mucosa in hyperplastic polyposis.
Minoo P, Baker K, Goswami R, Chong G, Foulkes WD, Ruszkiewicz AR, Barker M, Buchanan D, Young J, Jass JR.
Gut. 2006 Oct;55(10):1467-74. Epub 2006 Feb 9.
PMID 16469793
 
Aberrant methylation of multiple tumor suppressor genes in aging liver, chronic hepatitis, and hepatocellular carcinoma.
Nishida N, Nagasaka T, Nishimura T, Ikai I, Boland CR, Goel A.
Hepatology. 2008 Mar;47(3):908-18.
PMID 18161048
 
Genetic and epigenetic profiling in early colorectal tumors and prediction of invasive potential in pT1 (early invasive) colorectal cancers.
Nosho K, Yamamoto H, Takahashi T, Mikami M, Taniguchi H, Miyamoto N, Adachi Y, Arimura Y, Itoh F, Imai K, Shinomura Y.
Carcinogenesis. 2007 Jun;28(6):1364-70. Epub 2006 Dec 20.
PMID 17183069
 
High frequency somatic mutations in RASSF1A in nasopharyngeal carcinoma.
Pan ZG, Kashuba VI, Liu XQ, Shao JY, Zhang RH, Jiang JH, Guo C, Zabarovsky E, Ernberg I, Zeng YX.
Cancer Biol Ther. 2005 Oct;4(10):1116-22. Epub 2005 Oct 13.
PMID 16096369
 
DNA methylation biomarkers of prostate cancer: confirmation of candidates and evidence urine is the most sensitive body fluid for non-invasive detection.
Payne SR, Serth J, Schostak M, Kamradt J, Strauss A, Thelen P, Model F, Day JK, Liebenberg V, Morotti A, Yamamura S, Lograsso J, Sledziewski A, Semjonow A.
Prostate. 2009 Sep 1;69(12):1257-69.
PMID 19459176
 
Gene expression profiles in human cells submitted to genotoxic stress.
Sakamoto-Hojo ET, Mello SS, Pereira E, Fachin AL, Cardoso RS, Junta CM, Sandrin-Garcia P, Donadi EA, Passos GA.
Mutat Res. 2003 Nov;544(2-3):403-13.
PMID 14644343
 
The RASSF1A tumor suppressor activates Bax via MOAP-1.
Vos MD, Dallol A, Eckfeld K, Allen NP, Donninger H, Hesson LB, Calvisi D, Latif F, Clark GJ.
J Biol Chem. 2006 Feb 24;281(8):4557-63. Epub 2005 Dec 12.
PMID 16344548
 
RASSF2 is a novel K-Ras-specific effector and potential tumor suppressor.
Vos MD, Ellis CA, Elam C, Ulku AS, Taylor BJ, Clark GJ.
J Biol Chem. 2003 Jul 25;278(30):28045-51. Epub 2003 May 5.
PMID 12732644
 
Inactivation of RASSF2A by promoter methylation correlates with lymph node metastasis in nasopharyngeal carcinoma.
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Int J Cancer. 2007 Jan 1;120(1):32-8.
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Citation

This paper should be referenced as such :
Hesson, LB ; Latif, F
RASSF2 (Ras association (RalGDS/AF-6) domain family member 2)
Atlas Genet Cytogenet Oncol Haematol. 2010;14(7):652-661.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/RASSF2ID43461ch20p13.html


External links

Nomenclature
HGNC (Hugo)RASSF2   9883
Cards
AtlasRASSF2ID43461ch20p13
Entrez_Gene (NCBI)RASSF2  9770  Ras association domain family member 2
AliasesCENP-34; RASFADIN
GeneCards (Weizmann)RASSF2
Ensembl hg19 (Hinxton)ENSG00000101265 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000101265 [Gene_View]  chr20:4780024-4823645 [Contig_View]  RASSF2 [Vega]
ICGC DataPortalENSG00000101265
TCGA cBioPortalRASSF2
AceView (NCBI)RASSF2
Genatlas (Paris)RASSF2
WikiGenes9770
SOURCE (Princeton)RASSF2
Genetics Home Reference (NIH)RASSF2
Genomic and cartography
GoldenPath hg38 (UCSC)RASSF2  -     chr20:4780024-4823645 -  20p13   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)RASSF2  -     20p13   [Description]    (hg19-Feb_2009)
EnsemblRASSF2 - 20p13 [CytoView hg19]  RASSF2 - 20p13 [CytoView hg38]
Mapping of homologs : NCBIRASSF2 [Mapview hg19]  RASSF2 [Mapview hg38]
OMIM609492   
Gene and transcription
Genbank (Entrez)AK222650 AK291458 AK307232 AY154470 AY154471
RefSeq transcript (Entrez)NM_014737 NM_170774
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)RASSF2
Cluster EST : UnigeneHs.631504 [ NCBI ]
CGAP (NCI)Hs.631504
Alternative Splicing GalleryENSG00000101265
Gene ExpressionRASSF2 [ NCBI-GEO ]   RASSF2 [ EBI - ARRAY_EXPRESS ]   RASSF2 [ SEEK ]   RASSF2 [ MEM ]
Gene Expression Viewer (FireBrowse)RASSF2 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)9770
GTEX Portal (Tissue expression)RASSF2
Human Protein AtlasENSG00000101265-RASSF2 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP50749   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP50749  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP50749
Splice isoforms : SwissVarP50749
PhosPhoSitePlusP50749
Domaine pattern : Prosite (Expaxy)RA (PS50200)    SARAH (PS50951)   
Domains : Interpro (EBI)C-RASSF    RA_dom    RASSF2    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)RASSF2
DMDM Disease mutations9770
Blocks (Seattle)RASSF2
SuperfamilyP50749
Human Protein Atlas [tissue]ENSG00000101265-RASSF2 [tissue]
Peptide AtlasP50749
HPRD15218
IPIIPI00414179   IPI00217958   
Protein Interaction databases
DIP (DOE-UCLA)P50749
IntAct (EBI)P50749
FunCoupENSG00000101265
BioGRIDRASSF2
STRING (EMBL)RASSF2
ZODIACRASSF2
Ontologies - Pathways
QuickGOP50749
Ontology : AmiGOkinetochore  condensed chromosome kinetochore  skeletal system development  ossification  protein kinase activity  protein binding  nucleus  nucleoplasm  cytoplasm  Golgi apparatus  cytosol  protein phosphorylation  cell cycle  positive regulation of protein autophosphorylation  negative regulation of peptidyl-serine phosphorylation  epidermal growth factor receptor signaling pathway via I-kappaB kinase/NF-kappaB cascade  positive regulation of apoptotic process  protein complex  regulation of osteoblast differentiation  regulation of osteoclast differentiation  positive regulation of protein kinase activity  positive regulation of JNK cascade  bone remodeling  homeostasis of number of cells  protein stabilization  negative regulation of NIK/NF-kappaB signaling  
Ontology : EGO-EBIkinetochore  condensed chromosome kinetochore  skeletal system development  ossification  protein kinase activity  protein binding  nucleus  nucleoplasm  cytoplasm  Golgi apparatus  cytosol  protein phosphorylation  cell cycle  positive regulation of protein autophosphorylation  negative regulation of peptidyl-serine phosphorylation  epidermal growth factor receptor signaling pathway via I-kappaB kinase/NF-kappaB cascade  positive regulation of apoptotic process  protein complex  regulation of osteoblast differentiation  regulation of osteoclast differentiation  positive regulation of protein kinase activity  positive regulation of JNK cascade  bone remodeling  homeostasis of number of cells  protein stabilization  negative regulation of NIK/NF-kappaB signaling  4TR>
NDEx NetworkRASSF2
Atlas of Cancer Signalling NetworkRASSF2
Wikipedia pathwaysRASSF2
Orthology - Evolution
OrthoDB9770
GeneTree (enSembl)ENSG00000101265
Phylogenetic Trees/Animal Genes : TreeFamRASSF2
HOVERGENP50749
HOGENOMP50749
Homologs : HomoloGeneRASSF2
Homology/Alignments : Family Browser (UCSC)RASSF2
Gene fusions - Rearrangements
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerRASSF2 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)RASSF2
dbVarRASSF2
ClinVarRASSF2
1000_GenomesRASSF2 
Exome Variant ServerRASSF2
ExAC (Exome Aggregation Consortium)ENSG00000101265
GNOMAD BrowserENSG00000101265
Genetic variants : HAPMAP9770
Genomic Variants (DGV)RASSF2 [DGVbeta]
DECIPHERRASSF2 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisRASSF2 
Mutations
ICGC Data PortalRASSF2 
TCGA Data PortalRASSF2 
Broad Tumor PortalRASSF2
OASIS PortalRASSF2 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICRASSF2  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDRASSF2
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 RASSF2
DgiDB (Drug Gene Interaction Database)RASSF2
DoCM (Curated mutations)RASSF2 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)RASSF2 (select a term)
intoGenRASSF2
NCG5 (London)RASSF2
Cancer3DRASSF2(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM609492   
Orphanet
MedgenRASSF2
Genetic Testing Registry RASSF2
NextProtP50749 [Medical]
TSGene9770
GENETestsRASSF2
Target ValidationRASSF2
Huge Navigator RASSF2 [HugePedia]
snp3D : Map Gene to Disease9770
BioCentury BCIQRASSF2
ClinGenRASSF2
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD9770
Chemical/Pharm GKB GenePA34246
Clinical trialRASSF2
Miscellaneous
canSAR (ICR)RASSF2 (select the gene name)
Probes
Litterature
PubMed51 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineRASSF2
EVEXRASSF2
GoPubMedRASSF2
iHOPRASSF2
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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