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

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in Oncology and Haematology
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Gene Section
Review
RASSF6 (Ras association (RalGDS/AF-6) domain
family member 6)
Luke B Hesson, Farida Latif
Lowy Cancer Centre and Prince of Wales Clinical School, Faculty of Medicine, University of New South
Wales, NSW2052, Australia (LBH), School of Clinical and Experimental Medicine, College of Medical and
Dental Sciences, Department of Medical and Molecular Genetics, University of Birmingham, Birmingham
B15 2TT, UK (FL)
Published in Atlas Database: April 2010
Online updated version : http://AtlasGeneticsOncology.org/Genes/RASSF6ID43462ch4q13.html
DOI: 10.4267/2042/44939
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology
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).
Identity
Other names: DKFZp686K23225
HGNC (Hugo): RASSF6
Location: 4q13.3
Local order: Centromere-AFP-AFM-RASSF6-IL8Telomere.
Note
Brief overview : The RASSF family of tumour
suppressor genes (TSG) encode Ras superfamily
effector proteins that, amongst other functions, mediate
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.
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(1)
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RASSF6 (Ras association (RalGDS/AF-6) domain family member 6)
Hesson LB, Latif F
DNA/RNA
(TSA) in leukaemia cell lines in which RASSF6 is
epigenetically inactivated (Hesson et al., 2009).
Description
Expression
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 chr4:74,486,04574,486,258).
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.
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).
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
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.
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.
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(1)
48
RASSF6 (Ras association (RalGDS/AF-6) domain family member 6)
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 RASSF6induced 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-
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(1)
Hesson LB, Latif F
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 WW45dependent 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 MST2WW45 complex allows RASSF6-mediated and MST2mediated apoptosis (figure 3). The induction of
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RASSF6 (Ras association (RalGDS/AF-6) domain family member 6)
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 coimmunoprecipitation 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 RASSF6regulated apoptotic pathways that are triggered by the
activation of MST2 (figure 3).
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 MOAP1 (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 MOAP1 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.
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Hesson LB, Latif F
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.
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RASSF6 (Ras association (RalGDS/AF-6) domain family member 6)
Hesson LB, Latif F
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.
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(1)
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RASSF6 (Ras association (RalGDS/AF-6) domain family member 6)
Hesson LB, Latif F
Table 1: RASSF6 orthologues in model species.
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.
Mutations
Note
To date no inactivating mutations to RASSF6 have
been described.
Implicated in
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 longrange epigenetic silencing may account for RASSF6
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(1)
Pancreatic endocrine tumour
Note
RASSF6 is downregulated in the pancreatic endocrine
tumour cell line BON1 following siRNAi of Achaetescute complex-like 1 (ASCL1), a basic helix loop helix
(bHLH) transcription factor regulated by the NOTCH
signalling pathway (Johansson et al., 2009). ASCL1
52
RASSF6 (Ras association (RalGDS/AF-6) domain family member 6)
also negatively regulates expression of Dickkopf
homologue 1 (DKK1), an antagonist of the Wnt/betacatenin-dependent signalling pathway.
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.
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.
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This article should be referenced as such:
Zientek-Targosz H, Kunnev D, Hawthorn L, Venkov M, Matsui
S, Cheney RT, Ionov Y. Transformation of MCF-10A cells by
random mutagenesis with frameshift mutagen ICR191: a
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Hesson LB, Latif F. RASSF6 (Ras association (RalGDS/AF-6)
domain family member 6). Atlas Genet Cytogenet Oncol
Haematol. 2011; 15(1):47-54.
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