cbl mediated ligand-induced downregulation of egf receptors pathway
| PAG Title | cbl mediated ligand-induced downregulation of egf receptors pathway |
| PAG ID | WAG000008 |
| Type | P |
| Source Link |  BioCarta |
| Publication Reference | NA |
| PAG Description | As with many cell-surface receptors, activation of the EGF receptor can result in receptor interlization through receptor-mediated endocytosis, desensitizing further receptor sigling. 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 kise activity of activated growth factor receptor, and involves ubiquitition 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 ubiquitition ligases that label receptor for degradation. Cbl also recruits Cin85 to the receptor complex, and blocking Cin85 interaction blocks receptor interlization 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 sigling and also opposes cellular proliferation induced by EGF. EGF activation also appears to activate the tyrosine kise Src, which phosphorylates Cbl, and helps to activate the ubiquitition and degradation of EGF receptor. PKC activation and threonine phosphorylation of the EGF receptor can induce heterologous receptor interlization, 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 proteosome. 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 sigling means that it will have an important role in cellular transformation and the development and treatment of cancer. |
| Species | Homo sapiens |
| nCoCo Score | 1,745 |
| Base PAG ID | WAG000008 |
| Human Phenotyte Annotation | |
| Curator | PAGER curation team |
| Curator Contact | PAGER-contact@googlegroups.com |
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