Tumor suppressor C-RASSF proteins

Abstract

Human genome has ten genes that are collectedly called Ras association domain family (RASSF). RASSF is composed of two subclasses, C-RASSF and N-RASSF. Both N-RASSF and C-RASSF encode Ras association domain-containing proteins and are frequently suppressed by DNA hypermethylation in human cancers. However, C-RASSF and N-RASSF are quite different. Six C-RASSF proteins (RASSF1-6) are characterized by a C-terminal coiled-coil motif named Salvador/RASSF/Hippo domain, while four N-RASSF proteins (RASSF7-10) lack it. C-RASSF proteins interact with mammalian Ste20-like kinases-the core kinases of the tumor suppressor Hippo pathway-and cross-talk with this pathway. Some of them share the same interacting molecules such as MDM2 and exert the tumor suppressor role in similar manners. Nevertheless, each C-RASSF protein has distinct characters. In this review, we summarize our current knowledge of how C-RASSF proteins play tumor suppressor roles and discuss the similarities and differences among C-RASSF proteins.

Keywords: Apoptosis; Cell cycle; Hippo pathway; Ras; Tumor suppressor.

Fig. 1

Mammalian C-RASSF proteins. All C-RASSF proteins have Ras association (RA) and Salvador/RASSF/Hippo (SARAH) domains. RASSF1A and NORE1 carry a C1 domain. RASSF6 has a PDZ-binding motif

Fig. 2

Core architecture of Drosophila and the components of the mammalian Hippo pathway. The core components of the Drosophila Hippo pathway are depicted (left). Unphosphorylated Yorkie interacts with Scalloped in the nucleus. Hippo together with Mats and Salvador activates Warts. Activated Warts phosphorylates Yorkie. Phosphorylated Yorkie is trapped in the cytoplasm, where it undergoes degradation. Mammalian homologs are listed (right)