Ubiquitylation, trafficking and degradation of the Ron tyrosine kinase receptor

Abstract

Ron, the tyrosine kinase receptor for Macrophage Stimulating Protein (MSP) activates multiple intracellular signaling pathways promoting cell proliferation, motility, invasiveness and morphogenesis. Decoration of Receptor Tyrosine Kinases (RTKs) by ubiquitin is a signal for receptor internalization and routing to degradative compartments. Here we report the existence of a dual mechanism for Ron receptor downregulation. Ron is ubiquitylated in ligand-independent manner by the U-box E3 ligase CHIP (C-terminal Hsc70 interacting protein), recruited via chaperone intermediates Hsp90 and Hsc70. CHIP controls receptor turnover, as demonstrated by gene silencing experiments. Following ligand-induced activation, Ron recruits the negative regulator c-Cbl, which mediates receptor polyubiquitylation and degradation mostly via proteasome, in contrast with lysosomal-dependent degradation of multi-ubiquitilyated receptors. The molecular mechanisms regulating Ron trafficking to degradative compartments was assessed by function-impaired mutants or by gene silencing of chlatrin- or caveolin-dependent endocytosis. While chlatrin is not involved in receptor degradation, Ron can directly interact with caveolin-1 and interference with caveolae/raft-dependent endocytosis affects Ron sorting to degradative compartments. This research was supported by PRIN Italian Public Funding Agency.