Abstract
Humans have 10 genes that belong to the Ras association (RA) domain family (RASSF). Among them, RASSF7 to RASSF10 have the RA domain in the N-terminal region and are called the N-RASSF proteins. In contradistinction to them, RASSF1 to RASSF6 are referred to as the C-RASSF proteins. The C-RASSF proteins have the RA domain in the middle region and the Salvador/RASSF/Hippo domain in the C-terminal region. RASSF6 additionally harbors the PSD-95/Discs large/ZO-1 (PDZ)-binding motif. Expression of RASSF6 is epigenetically suppressed in human cancers and is generally regarded as a tumor suppressor. RASSF6 induces caspase-dependent and -independent apoptosis. RASSF6 interacts with mammalian Ste20-like kinases (homologs of Drosophila Hippo) and cross-talks with the Hippo pathway. RASSF6 binds MDM2 and regulates p53 expression. The interactions with Ras and Modulator of apoptosis 1 (MOAP1) are also suggested by heterologous protein-protein interaction experiments. RASSF6 regulates apoptosis and cell cycle through these protein-protein interactions, and is implicated in the NF-κB and JNK signaling pathways. We summarize our current knowledge about RASSF6 and discuss what common and different properties RASSF6 and the other C-RASSF proteins have.
Highlights
Humans have 10 genes that are collectively called Ras association domain family (RASSF) [1,2,3]
RASSF2, RASSF4, and RASSF6 inhibit MST2 under the same condition, and the chimera construct harboring the N-terminal region of RASSF1A and the C-terminal region of RASSF6 activates MST2, supporting that the activation of MST2 is specific for RASSF1A and is mediated by the N-terminal region of RASSF1A
Many, including us, have compared RASSF1A and RASSF6 in their properties as a tumor suppressor, their ability to interact with MDM2, their involvement in tumor necrosis factor-α (TNF-α) signaling and inflammation, as well as comparing them with Nore1- in the Ras-induced apoptosis
Summary
Humans have 10 genes that are collectively called Ras association domain family (RASSF) [1,2,3]. Six RASSF proteins, RASSF1 to RASSF6, have the Ras association (RA) domain in the middle region and the coiled-coil domain in the C-terminus. This C-terminal domain is named the Salvador/RASSF/Hippo (SARAH) domain, because Salvador and Hippo have this domain. The other four RASSF proteins, RASSF7 to RASSF10, have the RA domain in the N-terminal region and lack the SARAH domain [2]. The C-RASSF proteins have similar molecular structures and share the same interacting molecules. They are frequently silenced in human cancers and the low expression correlates with advanced stage and the poor prognosis [1,6]. We focus on RASSF6 and discuss the similarities and the differences between RASSF6 and the other C-RASSF proteins
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