c-Cbl is a critical modulator of the Ron tyrosine kinase receptor

Abstract

Ron, the receptor tyrosine kinase (RTK) for the macrophage stimulating protein (MSP), activates multiple signaling pathways by recruiting several positive regulators to a multifunctional docking site. Here we show that stimulation by MSP also recruits a negative regulator, the c-Cbl ubiquitin ligase, to the multifunctional docking site as well as to a juxtamembrane tyrosine autophosphorylation site. c-Cbl recruitment to these two sites results in polyubiquitylation of Ron molecules, which are subsequently sorted for endocytosis and degradation. Both the phosphotyrosine binding domain of c-Cbl and its RING domain are essential for downregulation of Ron. Although Ron and c-Cbl are found also in physical complexes that include Grb2, these associations are insufficient for productive ubiquitylation of Ron. Our results shed light on the mechanism of receptor desensitization mediated by c-Cbl and its binding partner Grb2.

RON(MST1R)is a novel prognostic marker and therapeutic target for gastroesophageal adenocarcinoma

“…Alteration of this molecule's ability to bind to membrane proteins plays a role in the stability and activation of various RTKs, including RON. 75 We describe here a novel R1018G mutation, to our knowledge not reported in any normal or malignant tissues to date, in the MST1R exon 13 juxtamembrane (JM) domain containing the conserved Cbl DpYR binding motif that occurred in 6 of 54 samples (11%)-none were observed in cell lines. A previous report defined this conserved motif, through artificial mutation, as a critical binding domain of Cbl initiated degradation of MET.…”

Endocytosis of Receptor Tyrosine Kinases

“…Cbl binds to and ubiquitinates EGFR, FGFR, PDGFR, VEGFR, CSF-1R, hepatocyte growth factor (c-Met), macrophage stimulating protein (Ron) and ephrin (EphR) receptors, as well as other RTKs (Levkowitz et al 1999;Miyake et al 1999;Wilhelmsen et al 2002;Duval et al 2003;Penengo et al 2003;Marmor and Yarden 2004;Fasen et al 2008). c-Cbl knockout, siRNA depletion of c-Cbl and Cblb, or overexpression of inactive Cbl mutants inhibit internalization of CSF-1R, EGFR, c-Kit, and several other RTKs (Lee et al 1999;Levkowitz et al 1999;Zeng et al 2005;Huang et al 2006).…”

Role of protein ubiquitylation in regulating endocytosis of receptor tyrosine kinases

“…c-Cbl functions in a stimulation-dependent manner to mediate the ubiquitylation of EGFR and promote its degradation (Joazeiro et al, 1999;Levkowitz et al, 1999;Waterman et al, 1999;Yokouchi et al, 1999a). cCbl also regulates multiple additional RTKs, including the receptors for the platelet-derived growth factor (PDGFR; Miyake et al, 1998), colony stimulating factor 1 (CSF-1R; Lee et al, 1999), ErbB-2 (Klapper et al, 2000), Met (Peschard et al, 2001) and Ron (Penengo et al, 2003), as well as cytokine receptors and the T-cell receptor. The E3 ligase activity of Cbl is regulated by ligand stimulation.…”