Differential localization of A-Raf regulates MST2-mediated Apoptosis during Epithelial Differentiation

Files in This Item:
 File SizeFormat
DownloadDifferential Localization of A-Raf Regulates MST2-mediated JRauch&WKolch.pdf2.9 MBAdobe PDF
Title: Differential localization of A-Raf regulates MST2-mediated Apoptosis during Epithelial Differentiation
Authors: Rauch, JensMack, B.McCann, BrendanVolinsky, NataliaBlanco-Fernandez, AlfonsoGires, 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: ApoptosisDifferentiationHNSCCBreast cancerKSR2A-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

Show full item record

SCOPUSTM   
Citations 50

7
Last Week
1
Last month
0
checked on Sep 12, 2020

Page view(s)

1,201
Last Week
4
Last month
15
checked on Aug 19, 2022

Download(s) 50

333
checked on Aug 19, 2022

Google ScholarTM

Check

Altmetric


If you are a publisher or author and have copyright concerns for any item, please email research.repository@ucd.ie and the item will be withdrawn immediately. The author or person responsible for depositing the article will be contacted within one business day.