Download Gene Section RASSF5 (Ras association (RalGDS/AF 6) domain family member 5)

Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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Gene Section
Short Communication
RASSF5 (Ras association (RalGDS/AF-6) domain
family member 5)
Lee Schmidt, Geoffrey J Clark
University of Louisville, Room 119C, Baxter II Research Building, 580 S Preston Street, Louisville, KY
40202, USA (LS, GJC)
Published in Atlas Database: October 2011
Online updated version : http://AtlasGeneticsOncology.org/Genes/RASSF5ID42059ch1q32.html
DOI: 10.4267/2042/47279
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
DNA/RNA
Other names: MGC10823, MGC17344, Maxp1,
NORE1, NORE1A, NORE1B, RAPL, RASSF3
HGNC (Hugo): RASSF5
Location: 1q32.1
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 prolinerich 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.
Note
Murine RASSF5 originally named Nore1a. Nore1B
independently identified and designated RAPL. Rat
RASSF5 also cloned independently and designated
Maxp1.
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 Nterminus. The total coding sequence for Isoform A is about 1260 bases with the other isoforms being smaller.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3)
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RASSF5 (Ras association (RalGDS/AF-6) domain family member 5)
Schmidt L, Clark GJ
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).
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3)
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RASSF5 (Ras association (RalGDS/AF-6) domain family member 5)
Schmidt L, Clark GJ
Protein
References
Description
Vavvas D, Li X, Avruch J, Zhang XF. Identification of Nore1 as
a potential Ras effector. J Biol Chem. 1998 Mar
6;273(10):5439-42
The full length cDNA (for isoform A) encodes for a 47kDa 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.
Khokhlatchev A, Rabizadeh S, Xavier R, Nedwidek M, Chen T,
Zhang XF, Seed B, Avruch J. Identification of a novel Rasregulated proapoptotic pathway. Curr Biol. 2002 Feb
19;12(4):253-65
Chen J, Lui WO, Vos MD, Clark GJ, Takahashi M, Schoumans
J, Khoo SK, Petillo D, Lavery T, Sugimura J, Astuti D, Zhang
C, Kagawa S, Maher ER, Larsson C, Alberts AS, Kanayama
HO, Teh BT. The t(1;3) breakpoint-spanning genes LSAMP
and NORE1 are involved in clear cell renal cell carcinomas.
Cancer Cell. 2003 Nov;4(5):405-13
Expression
Nore1a mRNA is expressed in the lung, kidney, liver,
brain, spleen, thymus and heart.
Hesson L, Dallol A, Minna JD, Maher ER, Latif F. NORE1A, a
homologue of RASSF1A tumour suppressor gene is
inactivated in human cancers. Oncogene. 2003 Feb
13;22(6):947-54
Localisation
It can be detected on microtubules, in the centrosome,
but appears most obvious in the nucleus.
Vos MD, Martinez A, Ellis CA, Vallecorsa T, Clark GJ. The proapoptotic Ras effector Nore1 may serve as a Ras-regulated
tumor suppressor in the lung. J Biol Chem. 2003 Jun
13;278(24):21938-43
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.
Aoyama Y, Avruch J, Zhang XF. Nore1 inhibits tumor cell
growth independent of Ras or the MST1/2 kinases. Oncogene.
2004 Apr 22;23(19):3426-33
Praskova M, Khoklatchev A, Ortiz-Vega S, Avruch J.
Regulation of the MST1 kinase by autophosphorylation, by the
growth inhibitory proteins, RASSF1 and NORE1, and by Ras.
Biochem J. 2004 Jul 15;381(Pt 2):453-62
Avruch J, Praskova M, Ortiz-Vega S, Liu M, Zhang XF. Nore1
and RASSF1 regulation of cell proliferation and of the MST1/2
kinases. Methods Enzymol. 2006;407:290-310
Calvisi DF, Ladu S, Gorden A, Farina M, Conner EA, Lee JS,
Factor VM, Thorgeirsson SS. Ubiquitous activation of Ras and
Jak/Stat pathways in human HCC. Gastroenterology. 2006
Apr;130(4):1117-28
Donninger H, Vos MD, Clark GJ. The RASSF1A tumor
suppressor. J Cell Sci. 2007 Sep 15;120(Pt 18):3163-72
Kumari G, Singhal PK, Rao MR, Mahalingam S. Nuclear
transport of Ras-associated tumor suppressor proteins:
different transport receptor binding specificities for arginine-rich
nuclear targeting signals. J Mol Biol. 2007 Apr 13;367(5):1294311
Mutations
Note
No tumor mutations yet reported.
Calvisi DF, Donninger H, Vos MD, Birrer MJ, Gordon L, Leaner
V, Clark GJ. NORE1A tumor suppressor candidate modulates
p21CIP1 via p53. Cancer Res. 2009 Jun 1;69(11):4629-37
Implicated in
Clear cell renal carcinoma
Richter AM, Pfeifer GP, Dammann RH. The RASSF proteins in
cancer; from epigenetic silencing to functional characterization.
Biochim Biophys Acta. 2009 Dec;1796(2):114-28
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.
Bee C, Moshnikova A, Mellor CD, Molloy JE, Koryakina Y,
Stieglitz B, Khokhlatchev A, Herrmann C. Growth and tumor
suppressor NORE1A is a regulatory node between Ras
signaling and microtubule nucleation. J Biol Chem. 2010 May
21;285(21):16258-66
Kumari G, Singhal PK, Suryaraja R, Mahalingam S. Functional
interaction of the Ras effector RASSF5 with the tyrosine kinase
Lck: critical role in nucleocytoplasmic transport and cell cycle
regulation. J Mol Biol. 2010 Mar 19;397(1):89-109
Various cancers
Note
Nore1a is frequently inactivated by promoter
methylation in renal carcinoma, breast cancer, lung
cancer, liver cancer and neurological tumors.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3)
Park J, Kang SI, Lee SY, Zhang XF, Kim MS, Beers LF, Lim
DS, Avruch J, Kim HS, Lee SB. Tumor suppressor ras
214
RASSF5 (Ras association (RalGDS/AF-6) domain family member 5)
association domain family 5 (RASSF5/NORE1) mediates death
receptor ligand-induced apoptosis. J Biol Chem. 2010 Nov
5;285(45):35029-38
This article should be referenced as such:
Schmidt L, Clark GJ. RASSF5 (Ras association (RalGDS/AF6) domain family member 5). Atlas Genet Cytogenet Oncol
Haematol. 2012; 16(3):212-215.
Overmeyer JH, Maltese WA. Death pathways triggered by
activated Ras in cancer cells. Front Biosci. 2011 Jan
1;16:1693-713
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3)
Schmidt L, Clark GJ
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