Differential localization of A-Raf regulates MST2-mediated Apoptosis during Epithelial Differentiation
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Title: | Differential localization of A-Raf regulates MST2-mediated Apoptosis during Epithelial Differentiation | Authors: | Rauch, Jens; Mack, B.; McCann, Brendan; Volinsky, Natalia; Blanco-Fernandez, Alfonso; Gires, O.; Kolch, Walter | Permanent link: | http://hdl.handle.net/10197/9156 | Date: | 19-Feb-2016 | Online since: | 2018-01-10T13:08:11Z | Abstract: | A-Raf belongs to the family of oncogenic Raf kinases that are involved in mitogenic signaling by activating the MEK-ERK pathway. Low kinase activity of A-Raf toward MEK suggested that A-Raf might have alternative functions. We recently identified A-Raf as a potent inhibitor of the proapoptotic mammalian sterile 20-like kinase (MST2) tumor suppressor pathway in several cancer entities including head and neck, colon, and breast. Independent of kinase activity, A-Raf binds to MST2 thereby efficiently inhibiting apoptosis. Here, we show that the interaction of A-Raf with the MST2 pathway is regulated by subcellular compartmentalization. Although in proliferating normal cells and tumor cells A-Raf localizes to the mitochondria, differentiated non-carcinogenic cells of head and neck epithelia, which express A-Raf at the plasma membrane. The constitutive or induced re-localization of A-Raf to the plasma membrane compromises its ability to efficiently sequester and inactivate MST2, thus rendering cells susceptible to apoptosis. Physiologically, A-Raf re-localizes to the plasma membrane upon epithelial differentiation in vivo. This re-distribution is regulated by the scaffold protein kinase suppressor of Ras 2 (KSR2). Downregulation of KSR2 during mammary epithelial cell differentiation or siRNA-mediated knockdown re-localizes A-Raf to the plasma membrane causing the release of MST2. By using the MCF7 cell differentiation system, we could demonstrate that overexpression of A-Raf in MCF7 cells, which induces differentiation. Our findings offer a new paradigm to understand how differential localization of Raf complexes affects diverse signaling functions in normal cells and carcinomas. | Funding Details: | Science Foundation Ireland | Type of material: | Journal Article | Publisher: | Springer Nature | Journal: | Cell Death and Differentiation | Volume: | 23 | Issue: | 8 | Start page: | 1283 | End page: | 1295 | Copyright (published version): | 2016 Springer Nature | Keywords: | Apoptosis; Differentiation; HNSCC; Breast cancer; KSR2; A-Raf | DOI: | 10.1038/cdd.2016.2 | Language: | en | Status of Item: | Peer reviewed | This item is made available under a Creative Commons License: | https://creativecommons.org/licenses/by-nc-nd/3.0/ie/ |
Appears in Collections: | Conway Institute Research Collection SBI Research Collection Medicine Research Collection |
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