Abstract
The Rassf1-6 polypeptides each contain a Ras/Rap association domain, which enables binding to several GTP-charged Ras-like GTPases, at least in vitro or when overexpressed. The Ras/Rap association domains are followed by SARAH domains, which mediate Rassf heterodimerization with the Mst1/2 protein kinases. Rassf1A is unequivocally a tumor suppressor, and all Rassf proteins behave like tumor suppressors, exhibiting epigenetic silencing of expression in many human cancers and pro-apoptotic and/or anti-proliferative effects when re-expressed in tumor cell lines. Herein, we review the binding of the Rassf polypeptides to Ras-like GTPases and the Mst1/2 kinases and their role in Rassf function.
Highlights
The Rassf (Ras association domain family) polypeptides, a family of non-catalytic proteins encoded by six genes, each expressed as multiple splice variants, were founded with the description of Nore1 as a Ras-GTPbinding protein [1]
Specific knock-outs of the exon encoding the unique N terminus of Rassf1A result in increased numbers of tumors in older mice, lymphomas, lung tumors, and gastrointestinal tumors [7, 8]; increased numbers of tumors have been reported in Rassf1A heterozygotes [7]
The Rassf polypeptides align into two groups; Rassf1, Rassf3, and Rassf5 (Nore1) exhibit ϳ50% amino acid sequence identity, whereas Rassf2 and Rassf4 are nearly 60% identical to each other and ϳ40% identical to Rassf6
Summary
Joseph Avruch‡§¶1, Ramnik Xavier¶ʈ**, Nabeel Bardeesy¶‡‡, Xian-feng Zhang‡§¶, Maria Praskova‡§¶, Dawang Zhou‡§¶, and Fan Xia‡§¶ From the ‡Department of Molecular Biology, §Diabetes and ʈGastrointestinal Units of the Medical Services, ‡‡Cancer Center, and **Center for Computational and Integrative Biology, Massachusetts General Hospital, and the ¶Department of Medicine, Harvard Medical School, Boston, Massachusetts 02114. Rassf1A is unequivocally a tumor suppressor, and all Rassf proteins behave like tumor suppressors, exhibiting epigenetic silencing of expression in many human cancers and proapoptotic and/or anti-proliferative effects when re-expressed in tumor cell lines. We review the binding of the Rassf polypeptides to Ras-like GTPases and the Mst1/2 kinases and their role in Rassf function. The Rassf (Ras association domain family) polypeptides, a family of non-catalytic proteins encoded by six genes, each expressed as multiple splice variants, were founded with the description of Nore ( designated Rassf5) as a Ras-GTPbinding protein [1]. This review will emphasize Nore1/Rassf and Rassf, the most extensively characterized members of the Rassf polypeptide family, focusing on their structure and binding to Ras-like GTPases and on the Mst1/2 protein kinases as likely physiologic effectors. Excellent recent reviews of the entire Rassf family in human cancers [6] and of Rassf1A [5] are recommended
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