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dc.contributor.authorOkur, Mustafa Nazir
dc.contributor.authorDoi, Jolene
dc.contributor.authorFong, Chee Wai
dc.contributor.authorMartinez, Natalia
dc.contributor.authorGarcia-Dominguez, Carlota
dc.contributor.authorRojas, Jose M.
dc.contributor.authorGuy, Graeme
dc.contributor.authorO'Bryana, John P.
dc.date.accessioned2012-04-15T04:04:51Z
dc.date.available2012-04-15T04:04:51Z
dc.date.issued2012-02
dc.identifier.bibliographicCitationOkur, M. N., Doi, J., Fong, C. W., Martinez, N., Garcia-Dominguez, C., Rojas, J. M., Guy, G., & O'Bryana, J. P. 2012. Intersectin 1 Enhances Cbl Ubiquitylation of Epidermal Growth Factor Receptor through Regulation of Sprouty2-Cbl Interaction. Molecular and Cellular Biology, 32(4): 817-825. DOI: 10.1128/MCB.05647-11en
dc.identifier.issn0270-7306
dc.identifier.otherDOI: 10.1128/MCB.05647-11
dc.identifier.urihttp://hdl.handle.net/10027/8263
dc.descriptionPost print version of article may differ from published version. The definitive version is available through Molecular and Cellular Biology © 2012 American Society for Microbiology. DOI: 10.1128/MCB.05647-11en
dc.description.abstractUbiquitylation 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.en
dc.description.sponsorshipThis work was funded in part by grants to JMR from FIS (PI09/0562), RETIC (RD06/0020/0003), and AECC and grants to J.P.O. from the NIH (RO1 HL090651), Department of Defense (PR080428), the Foundation Jerome Lejune, and the St. Baldrick’s Foundation.en
dc.language.isoen_USen
dc.publisherAmerican Society for Microbiologyen
dc.subjectreceptor tyrosine kinaseen
dc.subjectepidermal growth factor receptoren
dc.subjectubiquitylationen
dc.subjectendocytosisen
dc.titleIntersectin 1 Enhances Cbl Ubiquitylation of Epidermal Growth Factor Receptor through Regulation of Sprouty2-Cbl Interactionen
dc.typeArticleen


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