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Received for publication June 23, 2006.
Revised August 15, 2006.
Accepted for publication August 16, 2006.
Receptor tyrosine kinases (RTK) are critical for normal cell growth, differentiation and development but contribute to various pathological conditions when disrupted. Activation of RTKs stimulates a plethora of pathways, including the ubiquitylation and endocytosis of the receptor itself. Although endocytosis terminates RTK signaling, it has emerged as a requisite step in RTK activation of signaling pathways. Previously, we discovered that the endocytic scaffolding protein intersectin (ITSN) cooperated with EGFR in the regulation of cell growth and signaling. However, a biochemical link between ITSN and EGFR was not defined. In this study, we demonstrate that ITSN is a scaffold for the E3 ubiquitin ligase Cbl. ITSN forms a complex with Cbl in vivo mediated by the SH3 domains binding to the Pro-rich COOH-terminus of Cbl. This interaction stimulates the ubiquitylation and degradation of the activated EGFR. Furthermore, silencing ITSN by RNAi attenuated EGFR internalization as well as activation of the ERK-MAPK pathway thereby demonstrating the importance of ITSN in EGFR function. Given the cooperativity between ITSN and additional RTKs, these results point to an important evolutionarily conserved, regulatory role for ITSN in RTK function that is necessary for both signaling from receptors as well as the ultimate termination of receptor signaling.
Key words:
NGF/EGF, MAP Kinase, Fluorescence techniques, Immunocytochemistry, Mutagenesis/Chimeric approaches
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