A two-tiered mechanism of EGFR inhibition by RALT/MIG6 via kinase suppression and receptor degradation.
A two-tiered mechanism of EGFR inhibition by RALT/MIG6 via kinase suppression and receptor degradation.
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DOI：
10.1083/jcb.201002032
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发表时间：
2010-05-03
期刊：
影响因子：
--
通讯作者：
Segatto O
中科院分区：
文献类型：
--
作者：
Frosi Y;Anastasi S;Ballarò C;Varsano G;Castellani L;Maspero E;Polo S;Alemà S;Segatto O
EGFR激酶抑制剂RALT/MIG 6也作为内吞衔接子发挥作用，通过支架AP-2和interstins促进受体内化。表皮生长因子受体（EGFR）的信号转导必须严格控制，因为异常的EGFR活性可能导致细胞转化。受体相关晚期转导子（Receptor-associated late transducer，RALT）是EGFR的反馈抑制剂，其在小鼠中的基因消融由于EGFR驱动的过度细胞增殖而引起表型。RALT通过与EGFR激酶结构域对接抑制EGFR催化活化。我们在这里报告的RALT介导的EGFR抑制的另一种机制，表明RALT结合的EGF受体进行内吞作用，并最终降解成溶酶体。此外，RALT挽救不能进行内吞作用（Dc 214）或降解（Y1045 F）的EGFR突变体的内吞缺陷，并通过与负责EGFR催化抑制的结构域不同的结构域介导内吞作用。与为内吞蛋白提供支架功能一致，RALT通过结合AP-2和Intersectins驱动EGFR内吞。这些数据表明了一种模型，其中RALT与EGFR的结合整合了EGFR激酶的抑制与受体内吞作用和降解，导致EGFR信号传导的持久抑制。
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.
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