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 4^th (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.

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.

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

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

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.

No tumor mutations yet reported.