Nore1 and RASSF1 regulation of cell proliferation and of the MST1/2 kinases.
The six human Nore1/RASSF genes encode a family of putative tumor suppressor proteins, each expressed as multiple mRNA splice variants. The predominant isoforms of these noncatalytic polypeptides are characterized by the presence in their carboxyterminal segments of a Ras-Association (RA) domain followed by a SARAH domain. The expression of the RASSF1A and Nore1A isoforms is extinguished selectively by gene loss and/or epigenetic mechanisms in a considerable fraction of epithelial cancers and cell lines derived therefrom, and reexpression usually suppresses the proliferation and tumorigenicity of these cells. RASSF1A/Nore1A can cause cell cycle delay in G1 and/or M and may promote apoptosis. The founding member, Nore1A, binds preferentially through its RA domain to the GTP-charged forms of Ras, Rap-1, and several other Ras subfamily GTPases with high affinity. By contrast, RASSF1, despite an RA domain 50% identical to Nore1, exhibits relatively low affinity for Ras-like GTPases but may associate with Ras-GTP indirectly. Each of the RASSF polypeptides, including the C. elegans ortholog encoded by T24F1.3, binds to the Ste20-related protein kinases MST1 and MST2 through the SARAH domains of each partner. The recombinant MST1/2 kinases, spontaneous dimers, autoactivate in vitro through an intradimer transphosphorylation of the activation loop, and the Nore1/RASSF1 polypeptides inhibit this process. Recombinant MST1 is strongly activated in vivo by recruitment to the membrane; the recombinant MST1 that is bound to RasG12V through Nore1A is activated; however, the bulk of MST1 is not. Endogenous complexes of MST1 with both Nore1A and RASSF1A are detectable, and Nore1A/MST1 can associate with endogenous Ras in response to serum addition. Nevertheless, the physiological functions of the Nore1/RASSF polypeptides in mammalian cells, as well as the role of the MST1/2 kinases in their growth-suppressive actions, remain to be established. The Drosophila MST1/2 ortholog hippo is a negative regulator of cell cycle progression and is necessary for developmental apoptosis. Overexpression of mammalian MST1 or MST2 promotes apoptosis, as does overexpression of mutant active Ki-Ras. Interference with the ability of endogenous MST1/2 to associate with the Nore1/RASSF polypeptides inhibits Ras-induced apoptosis. At present, however, the relevance of Ki-Ras-induced apoptosis to the physiological functions of c-Ras and to the growth-regulating actions of spontaneously occurring oncogenic Ras mutants is not known.
Avruch
Joseph
J
Department of Molecular Biology and Diabetes Unit, Medical Services, Massachusetts General Hospital, USA.
Praskova
Maria
M
Ortiz-Vega
Sara
S
Liu
Matthew
M
Zhang
Xian-Feng
XF
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D051017:Apoptosis Regulatory Proteins; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism; D018288:Carcinoma, Small Cell / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation; D016193:G1 Phase / Q000187:drug effects; D000081410:Germinal Center Kinases; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007624:KB Cells; D020559:Monomeric GTP-Binding Proteins / Q000502:physiology*; D009369:Neoplasms / Q000503:physiopathology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D000090742:Serine-Threonine Kinase 3; D025521:Tumor Suppressor Proteins / Q000502:physiology*; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism; D018631:ras Proteins / Q000502:physiology; D000099317:Hippo Kinases
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D000081410:Germinal Center Kinases; D047908:Intracellular Signaling Peptides and Proteins; D020559:Monomeric GTP-Binding Proteins; D017346:Protein Serine-Threonine Kinases; D011994:Recombinant Proteins; D000090742:Serine-Threonine Kinase 3; D025521:Tumor Suppressor Proteins; D020827:rap1 GTP-Binding Proteins; D018631:ras Proteins; C411762:RASSF1 protein, human; C454042:RASSF5 protein, human; C095566:STK4 protein, human; D000099317:Hippo Kinases; C097835:STK3 protein, human