Cbl escapes Cdc42-mediated inhibition by downregulation of the adaptor molecule βPix

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Abstract
The Pix/Cool proteins are involved in the regulation of cell morphology by binding to small Rho GTPases and kinases of the Pak family. Recently, it has been shown that Pix/Cool-1 associates with the ubiquitin ligase Cbl, which appears to be a critical step in Cdc42-mediated inhibition of epidermal-growth-factor-receptor (EGFR) ubiquitylation and downregulation. Here we show that the SH3 domain of Pix specifically interacts with a proline–arginine motif (PxxxPR) present within the ubiquitin ligase Cbl and Pak1 kinase. Owing to targeting of the same sequence, Cbl and Pak1 compete for binding to Pix. In this complex, Cbl mediates ubiquitylation and subsequent degradation of Pix. Our findings reveal a double feedback loop in which the Cdc42/Pix complex blocks Cbl's ability to downregulate EGFR, while Cbl in turn promotes degradation of Pix in order to escape this inhibition. Such a relationship provides a mechanism to fine-tune the kinetics of RTK endocytosis and degradation depending on the pool of active Cdc42 and the duration of EGFR signaling.