Activated Cdc42 sequesters c-Cbl and prevents EGF receptor degradation.
Cdc42 is a Ras-related protein that has been implicated in the control of normal cell growth, and when improperly regulated, in cellular transformation and invasiveness. A variety of extracellular stimuli, including epidermal growth factor (EGF), activate Cdc42. Here, we show that activation of Cdc42 protects the EGF receptor from the negative regulatory activity of the c-Cbl ubiquitin ligase. Activated Cdc42 binds to p85Cool-1 (for cloned-out-of-library)/beta-Pix (for Pak-interactive exchange factor), a protein that directly associates with c-Cbl. This inhibits the binding of Cbl by the EGF receptor and thus prevents Cbl from catalyzing receptor ubiquitination. The role played by Cdc42 in regulating the timing of EGF receptor-Cbl interactions is underscored by the fact that constitutively active Cdc42(F28L), by persistently blocking the binding of Cbl to these receptors, leads to their aberrant accumulation and sustained EGF-stimulated ERK activation, thus resulting in cellular transformation.
D016475:3T3 Cells; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002455:Cell Division / Q000502:physiology*; D002462:Cell Membrane / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D025461:Feedback, Physiological / Q000502:physiology; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D050721:Proto-Oncogene Proteins c-cbl; D064067:Rho Guanine Nucleotide Exchange Factors; D044767:Ubiquitin-Protein Ligases; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
D018797:Cell Cycle Proteins; D020662:Guanine Nucleotide Exchange Factors; D011518:Proto-Oncogene Proteins; D064067:Rho Guanine Nucleotide Exchange Factors; D004815:Epidermal Growth Factor; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases; D020764:cdc42 GTP-Binding Protein; C493849:Cbl protein, mouse