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
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
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
Appears in Collections:Conway Institute Research Collection
SBI Research Collection
Medicine Research Collection

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