The RASSF1A tumor suppressor

Abstract

RASSF1A lacks apparent enzymatic activity but contains a Ras association (RA) domain and is potentially an effector of the Ras oncoprotein. RASSF1A modulates multiple apoptotic and cell cycle checkpoint pathways. Current evidence supports the hypothesis that it serves as a scaffold for the assembly of multiple tumor suppressor complexes and may relay pro-apoptotic signaling by KRas. RASSF1A is part of a family of potential tumor suppressorsRASSF1A is a member of a family of six related proteins, each of which exhibits multiple splice variants. With the exception of some minor splice variants, each protein contains an RA domain and a C-terminal SARAH protein-protein interaction motif. Each family member, with the exception of RASSF3, has now been implicated as a human tumor suppressor. RASSF5 (Nore1a) is the best characterized member of the family after RASSF1A. RASSF5 was the first member of the family cloned and it was originally designated Nore1a for novel Ras effector 1 (Vavvas et al., 1998). RASSF5 binds activated Ras directly and is present in an endogenous complex with Ras in cells. RASSF5 is pro-apoptotic and kills cells in a Ras-dependent manner (Khokhlatchev et al., 2002;Vos et al., 2003a). It is frequently inactivated in human tumors by promoter methylation (Table 2). Moreover, it is linked to the development of a rare familial form of cancer (Chen et al., 2003), which confirms its role as a tumor suppressor in vivo. Its mechanisms of action remain largely unknown, although it may regulate the pro-apoptotic kinase MST1 (Praskova et al., 2004). A smaller splice version of RASSF5 has been identified and designated Nore1b or RAPL (Katagiri et al., 2003;Tommasi et al., 2002). This protein demonstrates more restricted expression than RASSF5 and can form an endogenous complex with the Ras-related protein Rap. It regulates lymphocyte adhesion and has also been implicated as a tumor suppressor (Katagiri et al., 2003;Macheiner et al., 2006).RASSF2 is a pro-apoptotic Ras effector that is frequently downregulated in human tumors by promoter methylation, histone deacetylation and sometimes deletion (Akino et al., 2005; Endoh et al., 2005; Hesson et al., 2005; Lambros et al., 2005;Vos et al., 2003b). Inactivation of RASSF2 correlates with activation of Ras in tumor cells (Hesson et al., 2005). Reintroduction of RASSF2 into tumor cells impairs tumorigenesis and knocking down RASSF2 enhances tumorigenesis (Akino et al., 2005). Thus, RASSF2 also appears to be an epigenetically inactivated tumor suppressor. The effector pathways controlled by it remain unknown.RASSF3 can also bind to Ras and inhibit cell growth (unpublished observations). However, it is the only family member whose RNA is not downregulated in tumors (Tommasi et al., 2002). Whether it is involved in tumor suppression thus remains unknown. RASSF4 is frequently downregulated by promoter methylation in human tumor cells, binds to Ras and induces apoptosis. It localizes mostly to the cytosol but can be recruited to the plasma membrane by activated Ras ...

Itch E3 ubiquitin ligase regulates large tumor suppressor 1 stability

“…Significantly, mammalian homologs of each component of the Drosophila Hippo-LATS pathway have been identified [Fat4 for Fat, Merlin for Merlin, Ex for Ex, RASSF1A for dRASSF, hWW45 for Sav, Mst1 and Mst2 for Hippo, LATS1 and LATS2 for LATS, MOB1 (Msp1 one binder) for Mats, and YAP (Yesassociated protein) and TAZ (transcriptional coactivator with PDZ-binding motif) for Yorkie] (12). We and others recently showed that part of the Hippo-LATS signaling pathway discovered in Drosophila are conserved in mammals and that many members of the pathway could be confirmed as either tumor suppressors (Fat4, Merlin, RASSF1A, Mst1/2, LATS1/2, MOB1) or oncogenes (YAP and TAZ) in human cancers (15)(16)(17)(18)(19). Therefore, further characterization of Hippo-LATS pathway and its regulators in mammals will have great implication for not only our understanding the molecular mechanism of tumorigenesis, but also for future targeting of this pathway for cancer therapies.…”

Functional importance of RASSF1A microtubule localization and polymorphisms

“…RASSF1A, 1C, 5 and 7 have been demonstrated to associate with the microtubular network (Moshnikova et al, 2006(Moshnikova et al, , 2008Donninger et al, 2007;Sherwood et al, 2008;Richter et al, 2009). All have been shown to associate with centrosomal elements and, in the case of RASSF1A, with a-, g and b-tubulins.…”

Epigenetic inactivation of the RASSF10 candidate tumor suppressor gene is a frequent and an early event in gliomagenesis

“…Biologically, RASSF1A is also the best-characterized member of the group. RASSF1A is a bona fide tumor suppressor gene; RASSF1A knockout mice are prone to tumor development (Tommasi et al, 2005;van der Weyden et al, 2005), whereas RASSF1A protein is involved in microtubule stability, cell cycle progression, regulation of apoptosis, cell migration and forms a part of the mammalian Hippo tumor suppressor network (Donninger et al, 2007;Hesson et al, 2007b;Dallol et al, 2009). Some of the classical RASSF members have been shown to bind RAS proteins and hence may act as RAS effectors.…”