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...

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Bibliographic Details
Published in:Current biology 2007-04, Vol.17 (8), p.700-705
Main Authors: Guo, Cai, Tommasi, Stella, Liu, Limin, Yee, Jiing-Kuan, Dammann, Reinhard, Pfeifer, Gerd P.
Format: Article
Language:English
Subjects:
Animals
Cell Cycle Proteins - analysis
Cell Cycle Proteins - metabolism
CELLCYCLE
Centrosome
Cercopithecus aethiops
COS Cells
Drosophila
Embryo, Mammalian - cytology
Fibroblasts - metabolism
Humans
Mice
Mitosis
Phosphorylation
Protein-Serine-Threonine Kinases - analysis
Protein-Serine-Threonine Kinases - metabolism
Signal Transduction
SIGNALING
Spindle Apparatus - chemistry
Transfection
Tumor Suppressor Proteins - analysis
Tumor Suppressor Proteins - genetics
Tumor Suppressor Proteins - metabolism
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Summary: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.
ISSN:0960-9822
1879-0445
DOI:10.1016/j.cub.2007.02.055