Article

RASSF1A is part of a complex similar to the Drosophila Hippo/Salvador/Lats tumor-suppressor network.

Division of Biology, Beckman Research Institute of the City of Hope, Duarte, California 91010, USA.
Current Biology (Impact Factor: 9.92). 05/2007; 17(8):700-5. DOI: 10.1016/j.cub.2007.02.055
Source: PubMed

ABSTRACT 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.

0 Followers
 · 
73 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Over the past decade, discoveries on Hippo signaling have revealed a complex signaling network integrating various signaling pathways to modulate tissue homeostasis, organ size control, tissue repair, and regeneration. Malfunction of the Hippo pathway is associated with tumor and cancer development. Moreover, Hippo signaling has been proposed to act in numerous stem cells in a variety of organisms. Recently, more attention has been paid to define the functions of the Hippo pathway in tissue-specific stem cells, which have great potential to be used in cell-based therapies. Here we provide an overview of its roles in regulating stem cells in epithelial tissues and its potential implications in related cancers. © The Author 2014. Published by ABBS Editorial Office in association with Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences.
    Acta Biochimica et Biophysica Sinica 12/2014; DOI:10.1093/abbs/gmu111 · 2.09 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The Hippo pathway controls cell number and organ size by restricting cell proliferation and promoting apoptosis, and thus is a key regulator in development and homeostasis. Dysfunction of the Hippo pathway correlates with many pathological conditions, especially cancer. Hippo signaling also plays important roles in tissue regeneration and stem cell biology. Therefore, the Hippo pathway is recognized as a crucial target for cancer therapy and regeneration medicine. To date, structures of several key components in Hippo signaling have been determined. In this review, we summarize current available structural studies of the Hippo pathway, which may help to improve our understanding of its regulatory mechanisms, as well as to facilitate further functional studies and potential therapeutic interventions. © The Author 2014. Published by ABBS Editorial Office in association with Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences.
    Acta Biochimica et Biophysica Sinica 12/2014; DOI:10.1093/abbs/gmu107 · 2.09 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: RASSF1A may be the most frequently inactivated tumor suppressor yet identified in human cancer. It is a pro-apoptotic Ras effector and plays an important role in the apoptotic DNA damage response (DDR). We now show that in addition to DDR regulation, RASSF1A also plays a key role in the DNA repair process itself. We show RASSF1A forms a DNA damage regulated complex with the key DNA repair protein XPA. XPA requires RASSF1A to exert full repair activity and RASSF1A deficient cells exhibit an impaired ability to repair DNA. Moreover, a cancer associated RASSF1A SNP variant exhibits differential XPA binding and inhibits DNA repair. The interaction of XPA with other components of the repair complex, such as RPA, is controlled in part by a dynamic acetylation/deacetylation cycle. We found that RASSF1A and its SNP variant differentially regulate XPA protein acetylation and the SNP variant hyper-stabilizes the XPA/RPA-70 complex. Thus, we identify two novel functions for RASSF1A in the control of DNA repair and protein acetylation. As RASSF1A modulates both apoptotic DDR and DNA repair, it may play an important and unanticipated role in coordinating the balance between repair and death after DNA damage.
    Molecular and Cellular Biology 11/2014; 35(1). DOI:10.1128/MCB.00202-14 · 5.04 Impact Factor

Full-text (2 Sources)

Download
3 Downloads
Available from
Dec 19, 2014