Phosphorylation of CBL (EGFR:CBL) Binding of CBL to EGFR Sprouty lures membrane-bound CBL away from EGFR CDC42 lures CBL away from the receptor Beta-Pix pushes CIN85 away from CBL Localization of CBL:GRB2 to the membrane Phosphorylation of CBL (EGFR:GRB2:CBL) Ubiquitination of stimulated EGFR (CBL:GRB2) Sprouty lures cytosolic CBL away from EGFR CBL binds and ubiquitinates phosphorylated Sprouty Ubiquitination of stimulated EGFR (CBL) CBL binds to GRB2 Sprouty sequesters CBL away from active EGFR CBL ubiquitinates Sprouty CBL-mediated ubiquitination of CIN85 Assembly in clathrin-coated vesicles (CCVs) EGFR non-clathrin mediated endocytosis CBL escapes CDC42-mediated inhibition by down-regulating the adaptor molecule Beta-Pix Assembly of EGFR complex in clathrin-coated vesicles EGFR downregulation Authored: Castagnoli, L, 2006-10-10 13:09:34 GENE ONTOLOGYGO:0042059 Pubmed11283727 Pubmed14641021 Pubmed15021893 Reactome Database ID Release 43182971 Reactome, http://www.reactome.org ReactomeREACT_12484 Regulation of receptor tyrosine kinase (RTK) activity is implicated in the control of almost all cellular functions. One of the best understood RTKs is epidermal growth factor receptor (EGFR). Growth factors can bind to EGFR and activate it to initiate signalling cascades within the cell. EGFRs can also be recruited to clathrin-coated pits which can be internalised into endocytic vesicles. From here, EGFRs can either be recycled back to the plasma membrane or directed to lysosomes for destruction.This provides a mechanism by which EGFR signalling is negatively regulated and controls the strength and duration of EGFR-induced signals. It also prevents EGFR hyperactivation as commonly seen in tumorigenesis.<br><br>The proto-oncogene Cbl can negatively regulate EGFR signalling. The Cbl family of RING-type ubiquitin ligases are able to poly-ubiquitinate EGFR, an essential step in EGFR degradation. All Cbl proteins have a unique domain that recognises phosphorylated tyrosine residues on activated EGFRs. They also direct the ubiquitination and degradation of activated EGFRs by recruiting ubiquitin-conjugation enzymes. Cbl proteins function by specifically targeting activated EGFRs and mediating their down-regulation, thus providing a means by which signaling processes can be negatively regulated.<br><br>Cbl also promotes receptor internalization via it's interaction with an adaptor protein, CIN85 (Cbl-interacting protein of 85kDa). CIN85 binds to Cbl via it's SH3 domain and is enhanced by the EGFR-induced tyrosine phosphorylation of Cbl. The proline-rich region of CIN85 interacts with endophilins which are regulatory components of clathrin-coated vesicles (CCVs). Endophilins bind to membranes and induce membrane curvature, in conjunction with other proteins involved in CCV formation. The rapid recruitment of endophilin to the activated receptor complex by CIN85 is the mechanism which controls receptor internalization. Reviewed: Heldin, CH, 2008-02-12 09:44:02 PathwayStep3916 PathwayStep3917 PathwayStep3914 PathwayStep3915 PathwayStep3918 PathwayStep3919 PathwayStep3912 PathwayStep3913 PathwayStep3910 PathwayStep3911 PathwayStep3925 PathwayStep3920 PathwayStep3921 PathwayStep3922 PathwayStep3923 PathwayStep3924 PathwayStep3907 PathwayStep3908 PathwayStep3909