Abstract
Ubiquitylation of receptor tyrosine kinases plays a critical role in regulating the trafficking and lysosomal degradation of these important signaling molecules. We identified the multidomain scaffolding protein intersectin 1 (ITSN1) as an important regulator of this process (N. P. Martin et al., Mol. Pharmacol. 70:1463-1653, 2006) ITSN1 stimulates ubiquitylation of the epidermal growth factor receptor (EGFR) through enhancing the activity of the Cbl E3 ubiquitin ligase. However, the precise mechanism through which ITSN1 enhances Cbl activity was unclear. In this study, we found that ITSN1 enhances Cbl activity through disrupting the interaction of Cbl with the Sprouty2 (Spry2) inhibitory protein. We demonstrate that ITSN1 binds Pro-rich regions in both Cbl and Spry2 and that interaction of ITSN1 with Spry2 disrupts Spry2-Cbl interaction, resulting in enhanced ubiquitylation of the EGFR. Disruption of ITSN1 binding to Spry2 through point mutation of the Pro-rich ITSN1 binding site in Spry2 results in enhanced Cbl-Spry2 interaction and inhibition of receptor ubiquitylation. This study demonstrates that ITSN1 enhances Cbl activity by modulating the interaction of Cbl with Spry2. In addition, our results reveal a new level of complexity in the regulation of Cbl through the interaction with ITSN1 and Spry2.
Highlights
Ubiquitylation of receptor tyrosine kinases plays a critical role in regulating the trafficking and lysosomal degradation of these important signaling molecules
Binding of Cbl to activated Receptor tyrosine kinases (RTKs) represents an important step in regulation of RTK ubiquitylation, Cbl activity is modulated by both posttranslational modifications as well as interactions with numerous proteins [28]
We postulated that intersectin 1 (ITSN1) either promoted Cbl binding to an activator or prevented Cbl interaction with a negative regulator
Summary
Ubiquitylation of receptor tyrosine kinases plays a critical role in regulating the trafficking and lysosomal degradation of these important signaling molecules. 70:1463–1653, 2006) ITSN1 stimulates ubiquitylation of the epidermal growth factor receptor (EGFR) through enhancing the activity of the Cbl E3 ubiquitin ligase. A number of mechanisms exist to regulate the extent and duration of RTK signaling One such mechanism involves the covalent attachment of ubiquitin to activated receptors. Binding of Cbl to activated RTKs represents an important step in regulation of RTK ubiquitylation, Cbl activity is modulated by both posttranslational modifications as well as interactions with numerous proteins [28]. One such protein is the intersectin 1 (ITSN1) scaffold protein. Our results demonstrate that ITSN1 binds both Cbl and Spry and that ITSN1 releases Cbl from Spry inhibition, leading to enhanced EGFR ubiquitylation
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