The Ras association domain (RASSF) proteins are named due to the presence of a Ras association (RA) domain in their N or C terminus that can potentially interact with the Ras GTPase family of proteins. These GTPases control a variety of cellular processes, such as membrane trafficking, apoptosis, and proliferation. RASSF proteins contain several other functional domains that modulate associations with other proteins. RASSF proteins with the RA domain at the C terminus (which are termed C-terminal or classical RASSF) usually also include a Salvador-RASSF-Hippo (SARAH) domain involved in several protein-protein interactions and for homo- and heterodimerisation of RASSF isoforms. N-terminal RASSF proteins (with the RA domain in the N terminus) do not usually contain a SARAH domain [].At least 10 RASSF family members have been characterised (with multiple splice variants), many of which have been shown to play a role in tumour suppression. RASSF proteins also act as scaffolding agents in microtubule stability, regulate mitotic cell division, control cell migration and cell adhesion, and modulate NF-KB activity and the duration of inflammation. Loss of RASSF expression through promoter methylation has been shown in numerous types of cancer, including leukemia, melanoma, breast and prostate cancer [].RASSF5 is one of the C-terminal (also known as classical) RASSF proteins, characterised by an RA domain in the C terminus. RASSF5 is also referred to as NORE1 or RAPL, and is known to exist as at least three transcripts. RASSF5 is primarily involved in the control of apoptosis, through involvement in a number of different apoptosis pathways [, ], and functions as a tumor suppressor []. One transcript (A) has been suggested to be involved in developing the nervous system []. It has also been reported that RASSF5 is involved in the regulation of p27 localisation [].
The SARAH (Sav/Rassf/Hpo) domain is found at the C terminus in three classes of eukaryotic tumour suppressors that give the domain its name. In the Sav (Salvador) and Hpo (Hippo) families, the SARAH domain mediates signal transduction from Hpo via the Sav scaffolding protein to the downstream component Wts (Warts); the phosphorylation of Wts by Hpo triggers cell cycle arrest and apoptosis by down-regulating cyclin E, Diap 1 and other targets [, ]. The SARAH domain is also involved in dimerisation, as in the human Hpo orthologue, Mst1, which homodimerises via its C-terminal SARAH domain. The SARAH domain is found associated with other domains, such as protein kinase domains, WW/rsp5/WWP domain (), C1 domain (), LIM domain (), or the Ras-associating (RA) domain ().This entry represents the C-terminal SARAH domain of Mst1. The Mst1 SARAH domain interacts with Rassf1 and Rassf5 by forming a heterodimer which mediates the apoptosis process [].
