抄録
Signaling through receptor tyrosine kinases (RTKs) is implicated in the control of many cellular functions. Immediately following activation of RTKs, these receptors are rapidly translocated from cell surface into the endosomal compartment. Then, these are sorted into lysosomes for degradation. Recently, evidence is accumulating that numerous adaptor proteins are involved in RTKs downregulation by internalization and endocytosis. CIN85 (Cbl-interacting protein of 85 kDa) is a multiadaptor protein containing three Src homology 3 (SH3) domains, a proline-rich region and a coiled-coil domain. Here we show that CIN85 is involved in regulation of ligand-induced endocytosis of epidermal growth factor (EGF) receptors. CIN85 is monoubiquitinated by Cbl/Cbl-b after EGF stimulation. Monoubiquitination is thought to regulate receptor internalization and endosomal sorting. Monoubiquitination of CIN85 required direct interaction between CIN85 and Cbl, the intact RING finger domain of Cbl and a ubiquitin acceptor site present in the carboxyl terminus of CIN85. CIN85 was also found in the complex with Cbl and polyubiquitinated EGF receptors, leading to their common degradation in the lysosome. Taken together, our results indicate that Cbl can mediate monoubiquitination of CIN85 to control endosomal sorting and degradation of RTKs. To analyze the biological function of CIN85 in vivo, we generated mutant mice deficient in the expression of CIN85. The phenotype of CIN85 knock-out mice is under investigation. [J Physiol Sci. 2007;57 Suppl:S225]
