RASSF1A is part of a complex similar to the Drosophila Hippo/Salvador/Lats tumor-suppressor network.
The Ras Association Domain Family 1A (RASSF1A) gene is one of the most frequently silenced genes in human cancer. RASSF1A has been shown to interact with the proapoptotic kinase MST1. Recent work in Drosophila has led to the discovery of a new tumor-suppressor pathway involving the Drosophila MST1 and MST2 ortholog, Hippo, as well as the Lats/Warts serine/threonine kinase and a protein named Salvador (Sav). Little is known about this pathway in mammalian cells. We report that complexes consisting of RASSF1A, MST2, WW45 (the human ortholog of Sav), and LATS1 exist in human cells. MST2 enhances the RASSF1A-WW45 interaction, which requires the C-terminal SARAH domain of both proteins. Components of this complex are localized at centrosomes and spindle poles from interphase to telophase and at the midbody during cytokinesis. Both RASSF1A and WW45 activate MST2 by promoting MST2 autophosphorylation and LATS1 phosphorylation. Mitosis is delayed in Rassf1a(-/-) mouse embryo fibroblasts and frequently results in cytokinesis failure, similar to what has been observed for LATS1-deficient cells. RASSF1A, MST2, or WW45 can rescue this defect. The complex of RASSF1A, MST2, WW45, and LATS1 consists of several tumor suppressors, is conserved in mammalian cells, and appears to be involved in controlling mitotic exit.
Guo
Cai
C
Division of Biology, Beckman Research Institute of the City of Hope, Duarte, California 91010, USA.
Tommasi
Stella
S
Liu
Limin
L
Yee
Jiing-Kuan
JK
Dammann
Reinhard
R
Pfeifer
Gerd P
GP
D000818:Animals; D019556:COS Cells; D018797:Cell Cycle Proteins / Q000032:analysis / Q000378:metabolism; D018385:Centrosome; D002522:Chlorocebus aethiops; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D051379:Mice; D008938:Mitosis; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000032:analysis / Q000378:metabolism; D000090742:Serine-Threonine Kinase 3; D015398:Signal Transduction; D008941:Spindle Apparatus / Q000737:chemistry; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D000099317:Hippo Kinases
D018797:Cell Cycle Proteins; D017346:Protein Serine-Threonine Kinases; D000090742:Serine-Threonine Kinase 3; D025521:Tumor Suppressor Proteins; C411762:RASSF1 protein, human; C415864:SAV1 protein, human; C092745:LATS1 protein, human; C097835:STK3 protein, human; D000099317:Hippo Kinases