A two-tiered mechanism of EGFR inhibition by RALT/MIG6 via kinase suppression and receptor degradation
| Autor: | Simona Polo, Oreste Segatto, Giulia Varsano, Stefano Alemà, Loriana Castellani, Elena Maspero, Costanza Ballarò, Yuri Frosi, Sergio Anastasi |
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| Rok vydání: | 2010 |
| Předmět: |
biology
Cell growth Kinase education Phosphotransferases Endocytic cycle Intracellular Signaling Peptides and Proteins Signal transducing adaptor protein Cell Biology Endocytosis Article Cell biology ErbB Receptors Mice Protein kinase domain Mutation biology.protein Animals Epidermal growth factor receptor Signal transduction health care economics and organizations Research Articles Cells Cultured Adaptor Proteins Signal Transducing Signal Transduction |
| Zdroj: | The Journal of Cell Biology |
| ISSN: | 1540-8140 0021-9525 |
| DOI: | 10.1083/jcb.201002032 |
| Popis: | The EGFR kinase inhibitor RALT/MIG6 also functions as an endocytic adaptor to promote receptor internalization by scaffolding AP-2 and intersectins. Signaling by epidermal growth factor receptor (EGFR) must be controlled tightly because aberrant EGFR activity may cause cell transformation. Receptor-associated late transducer (RALT) is a feedback inhibitor of EGFR whose genetic ablation in the mouse causes phenotypes due to EGFR-driven excess cell proliferation. RALT inhibits EGFR catalytic activation by docking onto EGFR kinase domain. We report here an additional mechanism of EGFR suppression mediated by RALT, demonstrating that RALT-bound EGF receptors undergo endocytosis and eventual degradation into lysosomes. Moreover, RALT rescues the endocytic deficit of EGFR mutants unable to undergo either endocytosis (Dc214) or degradation (Y1045F) and mediates endocytosis via a domain distinct from that responsible for EGFR catalytic suppression. Consistent with providing a scaffolding function for endocytic proteins, RALT drives EGFR endocytosis by binding to AP-2 and Intersectins. These data suggest a model in which binding of RALT to EGFR integrates suppression of EGFR kinase with receptor endocytosis and degradation, leading to durable repression of EGFR signaling. |
| Databáze: | OpenAIRE |
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