About: EGF Receptor Downregulation by CBL Pathway

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Attributes	Values
rdf:type	Class
rdfs:label	EGF Receptor Downregulation by CBL Pathway
rdfs:subClassOf	Regulatory Pathway
Semantic_Type	Functional Concept
Preferred_Name	EGF Receptor Downregulation by CBL Pathway
UMLS_CUI	C1512119
BioCarta_ID	h_cblPathway
ALT_DEFINITION	As with many cell-surface receptors, activation of the EGF receptor can result in receptor internalization through receptor-mediated endocytosis, desensitizing further receptor signaling. This process requires clathrin and occurs in clathrin-coated pits, which pinch off from the plasma membrane to form vesicles that move to the early endosome. From the early endosome, receptors can either be recycled back to the cell surface, or they can move through the late endosome to the lysosome for proteolytic degradation. The sorting of receptors in the early endosome for degradation requires the tyrosine kinase activity of activated growth factor receptor and involves ubiquitination of the receptor. Targeting of receptors for degradation requires members of the Cbl gene family. Cbl proteins bind to tyrosine phosphorylated EGF receptor, and are E3 ubiquitination ligases that label receptor for degradation. Cbl also recruits Cin85 to the receptor complex, and blocking Cin85 interaction blocks receptor internalization and degradation. Endophilins are also a member of this receptor-bound protein complex. In its role as a ubiquitin ligase and docking protein, Cbl desensitizes EGF signaling and also opposes cellular proliferation induced by EGF. EGF activation also appears to activate the tyrosine kinase Src, which phosphorylates Cbl, and helps to activate the ubiquitination and degradation of EGF receptor. PKC activation and threonine phosphorylation of the EGF receptor can induce heterologous receptor internalization, but opposes Cbl-mediated receptor degradation. PKC phosphorylated receptors are sorted for recycling to the cell surface, and directed away from the late endosome and proteasome. Other growth factor receptors are regulated in a similar manner, including the PDGF receptor, HGF receptor and the CSF-1 receptor, indicating that this is a fairly general regulatory mechanism. The importance of Cbl in the down-regulation of growth factor signaling means that it will have an important role in cellular transformation and the development and treatment of cancer.BIOCARTA
Legacy_Concept_Name	EGF_Receptor_Downregulation_by_CBL_Pathway
FULL_SYN	CBL mediated ligand-induced downregulation of EGF receptorsPTBIOCARTA EGF Receptor Downregulation by CBL PathwayPTNCI
code	C39016
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