A two-tiered mechanism of EGFR inhibition by RALT/MIG6 via kinase suppression and receptor degradation

被引:96
作者
Frosi, Yuri [1 ]
Anastasi, Sergio [1 ]
Ballaro, Costanza [2 ]
Varsano, Giulia [1 ]
Castellani, Loriana [2 ,3 ]
Maspero, Elena [4 ]
Polo, Simona [4 ,5 ]
Alema, Stefano [2 ]
Segatto, Oreste [1 ]
机构
[1] Ist Regina Elena, I-00158 Rome, Italy
[2] CNR, Ist Biol Cellulare, I-00016 Monterotondo, Italy
[3] Univ Cassino, Dipartimento Sci Motorie & Salute, I-03043 Cassino, Italy
[4] Fdn Ist FIRC Oncol Mol, Ist IFOM, I-20139 Milan, Italy
[5] Univ Milan, Dipartimento Med Chirurg & Odontoiatria, I-20142 Milan, Italy
关键词
EPIDERMAL-GROWTH-FACTOR; CLATHRIN-COATED PITS; TARGETED EXPRESSION; NEGATIVE REGULATOR; TYROSINE KINASES; ADAPTER PROTEIN; ENDOCYTOSIS; INTERNALIZATION; DOMAIN; INTERSECTIN;
D O I
10.1083/jcb.201002032
中图分类号
Q2 [细胞生物学];
学科分类号
071013 [干细胞生物学];
摘要
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.
引用
收藏
页码:557 / 571
页数:15
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