Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA.
Mol Biol Cell. 2012 Sep;23(18):3602-11. doi: 10.1091/mbc.E11-08-0666. Epub 2012 Jul 25.
Ubiquitination of the epidermal growth factor receptor (EGFR) by cbl and its cognate adaptor cbl-interacting protein of 85 kDa (CIN85) is known to play an essential role in directing this receptor to the lysosome for degradation. The mechanisms by which this ubiquitin modification is regulated are not fully defined, nor is it clear where this process occurs. In this study we show that EGFR activation leads to a pronounced src-mediated tyrosine phosphorylation of CIN85 that subsequently influences EGFR ubiquitination. Of importance, phospho-CIN85 interacts with the Rab5-positive endosome, where it mediates the sequestration of the ubiquitinated receptor into multivesicular bodies (MVBs) for subsequent degradation. These findings provide novel insights into how src- kinase-based regulation of a cbl adaptor regulates the fate of the EGFR.
泛素化的表皮生长因子受体（ EGFR ）的 cbl 和它的同源衔接蛋白 cbl-interacting 蛋白 85kDa （ CIN85 ）被认为在指导该受体溶酶体降解方面起着至关重要的作用。这种泛素化修饰的调控机制尚不完全明确，也不清楚这个过程发生在哪里。在这项研究中，我们发现 EGFR 的激活导致明显的 src 介导的 CIN85 的酪氨酸磷酸化，随后影响 EGFR 的泛素化。重要的是，磷酸化的 CIN85 与 Rab5 阳性内涵体相互作用，在那里它介导将泛素化的受体隔离到多泡体（ MVBs ）中进行随后的降解。这些发现为 src 激酶调节 cbl 衔接蛋白如何调节 EGFR 的命运提供了新的见解。
