Direct binding of Cbl to Tyr 568} and Tyr 936} of the stem cell factor receptor/c-Kit is required for ligand-induced ubiquitination, internalization and degradation

Kristina Masson , Elke Heiss , Hamid Band , Lars Rönnstrand (1)

1 Experimental Clinical Chemistry, Dept. of Laboratory Medicine

The ubiquitin E3 ligase Cbl has been shown to negatively regulate tyrosine kinase receptors, including the stem cell factor receptor/c-Kit. Impaired recruitment of Cbl to c-Kit results in a deregulated positive signaling that eventually can contribute to carcinogenesis. Here we present data showing that Cbl is activated by the Src family kinases and recruited to c-Kit in order to trigger receptor ubiquitination. We demonstrate that phosphorylated Y568 and Y936 in c-Kit are involved in direct binding and activation of Cbl and that binding of the TKB domain of Cbl to c-Kit is specified by the presence of an isoleucine or leucine residue in position +3 to the phosphorylated tyrosine residue on c-Kit. Apart from the direct association between Cbl and c-Kit, we show that phosphorylation of Cbl by Src family kinase members is required for activation of Cbl to occur. Moreover, we demonstrate that Cbl mediates monoubiquitination of c-Kit and that the receptor is subsequently targeted for lysosomal degradation. Taken together, our findings reveal novel insights into the mechanisms by which Cbl negatively regulates c-Kit mediated signaling.

Mots clés: Life Sciences

Kristina Masson, Elke Heiss, Hamid Band, Lars Rönnstrand. Direct binding of Cbl to Tyr 568} and Tyr 936} of the stem cell factor receptor/c-Kit is required for ligand-induced ubiquitination, internalization and degradation. Biochemical Journal, 2006, 399 (1), pp.59-67. ⟨10.1042/BJ20060464⟩. ⟨hal-00478567⟩