Janas, J. A., Van Aelst, L. (May 2011) Oncogenic tyrosine kinases target Dok-1 for ubiquitin-mediated proteasomal degradation to promote cell transformation. Molecular and Cellular Biology, 31 (13). pp. 2552-2565. ISSN 0270-7306
Preview |
PDF (Paper)
Van Aelst Molecular and Cellular Biology 2011.pdf - Published Version Download (1MB) | Preview |
Abstract
Cellular transformation induced by oncogenic tyrosine kinases is a multi-step process involving activation of growth-promoting signaling pathways and inactivation of suppressor molecules. Dok-1 is an adaptor protein that acts as a negative regulator of tyrosine kinase-initiated signaling and opposes oncogenic tyrosine kinase-mediated cell transformation. Findings that its loss facilitates transformation induced by oncogenic tyrosine kinases suggest that Dok-1 inactivation could constitute an intermediate step in oncogenesis driven by these oncoproteins. However, whether Dok-1 is subject to regulation by oncogenic tyrosine kinases remained unknown. In this study we show that oncogenic tyrosine kinases, including p210(bcr-abl) and oncogenic forms of Src, down-regulate Dok-1 by targeting it for degradation through the ubiquitin-proteasome pathway. This process is dependent on the tyrosine kinase activity of the oncoproteins, and is mediated primarily by lysine-dependent polyubiquitination of Dok-1. Importantly, restoration of Dok-1 levels strongly suppresses transformation of cells expressing oncogenic tyrosine kinases, and this suppression is more pronounced in the context of a Dok-1 mutant that is largely refractory to oncogenic tyrosine kinases-induced degradation. Our findings suggest that proteasome-mediated down-regulation of Dok-1 is a key mechanism by which oncogenic tyrosine kinases overcome the inhibitory effect of Dok-1 on cellular transformation and tumor progression.
Actions (login required)
 |
Administrator's edit/view item |