RASSF5 (Ras association (RalGDS/AF-6) domain family member 5)

2011-10-01   Lee Schmidt , Geoffrey J Clark 

University of Louisville, Room 119C, Baxter II Research Building, 580 S Preston Street, Louisville, KY 40202, USA

Identity

HGNC
LOCATION
1q32.1
IMAGE
Atlas Image
LOCUSID
ALIAS
Maxp1,NORE1,NORE1A,NORE1B,RAPL,RASSF3
FUSION GENES

DNA/RNA

Atlas Image
Figure 1. Isoform A is shown as the longest isoform with 6 exons. Isoform B, without an alternate exon, shows that the frameshift gives a shortened and unique C-terminus. Isoform C is shown with a special 5 UTR and lacks an in-frame coding region leading to a unique N-terminus. The total coding sequence for Isoform A is about 1260 bases with the other isoforms being smaller.

Description

The human gene for RASSF5 is 81 kb in length and is located on chromosome 1(q32.1). The gene can produce 4 protein isoforms, two via differential exon usage, a third via differential promoter usage and the genesis of the 4th (which can be found as an EST clone) is not yet clear. The largest isoform, A, is 418 amino acids long and has a molecular weight of about 47 kD. The protein structure of RASSF5A contains a proline-rich region at the N-terminus which contains potential SH3 binding sites and a nuclear localization signal. This is followed by a cystein rich domain, sometimes referred to as a zinc finger. Next is the Ras association domain and this is followed by sequence containing the SARAH motif required for binding to the pro-apoptotic kinases MST1 and MST2. A second nuclear localization sequence has been reported between amino acids 200-260 and a nuclear export sequence between amino acids 260-300.

Proteins

Atlas Image
Figure 2. A figure showing the processed mRNA as well as the amino acid sequence for isoforms A-D followed by motif explanation of isoform A (Nore1a).

Description

The full length cDNA (for isoform A) encodes for a 47-kDa protein which contains a proline-rich region at the N-terminus followed by a putative diacylglycerol/phorbol ester binding domain. This is followed by the Ras association (RA) domain and then the domain containing a SARAH motif. This later is responsible for binding to the pro-apoptotic kinases MST1 and MST2.

Expression

Nore1a mRNA is expressed in the lung, kidney, liver, brain, spleen, thymus and heart.

Localisation

It can be detected on microtubules, in the centrosome, but appears most obvious in the nucleus.

Function

RASSF5A is a pro-apoptotic Ras effector that can bind and relocalize the pro-apoptotic MST kinases in the presence of activated Ras. It can also promote cell cycle arrest and modulate the activity of p53 by regulating its nuclear localization. Knockdown of RASSF5A promotes cellular proliferation and soft agar growth. Thus, RASSF5A appears to function as a Ras regulated tumor suppressor. Analysis of human tumors has found little evidence of somatic mutation but the gene is frequently inactivated by promoter methylation in a broad range of human tumors. RASSF5C (also known as Nore1b or RAPL) has been reported to modulate cellular adhesion and to be regulated by the Ras related protein Rap1a. RASSF5C has also been implicated as serving as an adaptor protein to facilitate the interaction of Ras and CARMA1.

Mutations

Note

No tumor mutations yet reported.

Implicated in

Entity name
Clear cell renal carcinoma
Note
RASSF5 is frequently down-regulated by promoter methylation in a variety of tumors including clear cell renal carcinomas. Moreover, a rare hereditary form of kidney cancer has been reported that maps with a translocation inactivating the RASSF5 gene.
Entity name
Various cancers
Note
Nore1a is frequently inactivated by promoter methylation in renal carcinoma, breast cancer, lung cancer, liver cancer and neurological tumors.

Bibliography

Pubmed IDLast YearTitleAuthors
150073832004Nore1 inhibits tumor cell growth independent of Ras or the MST1/2 kinases.Aoyama Y et al
167573332006Nore1 and RASSF1 regulation of cell proliferation and of the MST1/2 kinases.Avruch J et al
203390012010Growth and tumor suppressor NORE1A is a regulatory node between Ras signaling and microtubule nucleation.Bee C et al
194359142009NORE1A tumor suppressor candidate modulates p21CIP1 via p53.Calvisi DF et al
146675072003The t(1;3) breakpoint-spanning genes LSAMP and NORE1 are involved in clear cell renal cell carcinomas.Chen J et al
178782332007The RASSF1A tumor suppressor.Donninger H et al
125845742003NORE1A, a homologue of RASSF1A tumour suppressor gene is inactivated in human cancers.Hesson L et al
118645652002Identification of a novel Ras-regulated proapoptotic pathway.Khokhlatchev A et al
200645232010Functional interaction of the Ras effector RASSF5 with the tyrosine kinase Lck: critical role in nucleocytoplasmic transport and cell cycle regulation.Kumari G et al
211962572011Death pathways triggered by activated Ras in cancer cells.Overmeyer JH et al
208106632010Tumor suppressor ras association domain family 5 (RASSF5/NORE1) mediates death receptor ligand-induced apoptosis.Park J et al
151093052004Regulation of the MST1 kinase by autophosphorylation, by the growth inhibitory proteins, RASSF1 and NORE1, and by Ras.Praskova M et al
193447522009The RASSF proteins in cancer; from epigenetic silencing to functional characterization.Richter AM et al
94886631998Identification of Nore1 as a potential Ras effector.Vavvas D et al
126769522003The pro-apoptotic Ras effector Nore1 may serve as a Ras-regulated tumor suppressor in the lung.Vos MD et al

Other Information

Locus ID:

NCBI: 83593
MIM: 607020
HGNC: 17609
Ensembl: ENSG00000266094

Variants:

dbSNP: 83593
ClinVar: 83593
TCGA: ENSG00000266094
COSMIC: RASSF5

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000266094ENST00000577571Q8WWW0
ENSG00000266094ENST00000579436Q8WWW0
ENSG00000266094ENST00000580449Q8WWW0
ENSG00000266094ENST00000581503A0A075B763
ENSG00000266094ENST00000581888Q8TEK8
ENSG00000266094ENST00000636182A0A1B0GTG4

Expression (GTEx)

0
10
20
30
40
50
60
70
80

Pathways

PathwaySourceExternal ID
Leukocyte transendothelial migrationKEGGko04670
Non-small cell lung cancerKEGGko05223
Leukocyte transendothelial migrationKEGGhsa04670
Pathways in cancerKEGGhsa05200
Non-small cell lung cancerKEGGhsa05223
Ras signaling pathwayKEGGhsa04014
Rap1 signaling pathwayKEGGhsa04015
Rap1 signaling pathwayKEGGko04015

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
203796142010Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.62
203467072010T cell receptor "inside-out" pathway via signaling module SKAP1-RapL regulates T cell motility and interactions in lymph nodes.49
185966992008Novel type of Ras effector interaction established between tumour suppressor NORE1A and Ras switch II.47
239724702013Structural basis for autoactivation of human Mst2 kinase and its regulation by RASSF5.35
126769522003The pro-apoptotic Ras effector Nore1 may serve as a Ras-regulated tumor suppressor in the lung.34
202374962010New genetic associations detected in a host response study to hepatitis B vaccine.27
194359142009NORE1A tumor suppressor candidate modulates p21CIP1 via p53.26
155696732005Local activation of Rap1 contributes to directional vascular endothelial cell migration accompanied by extension of microtubules on which RAPL, a Rap1-associating molecule, localizes.24
216698742011SKAP1 protein PH domain determines RapL membrane localization and Rap1 protein complex formation for T cell receptor (TCR) activation of LFA-1.23
226951702012The RASSF gene family members RASSF5, RASSF6 and RASSF7 show frequent DNA methylation in neuroblastoma.23

Citation

Lee Schmidt ; Geoffrey J Clark

RASSF5 (Ras association (RalGDS/AF-6) domain family member 5)

Atlas Genet Cytogenet Oncol Haematol. 2011-10-01

Online version: http://atlasgeneticsoncology.org/gene/42059/rassf5