Endogenous cAbl regulates receptor endocytosis
Endogenous cAbl regulates receptor endocytosis
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DOI：
10.1016/j.cellsig.2009.03.016
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发表时间：
2009-08-01
影响因子：
4.8
通讯作者：
Pure, Ellen
中科院分区：
文献类型：
--
作者：
Jacob, Michele;Todd, Leslie A.;Pure, Ellen
配体诱导的受体内吞作用有两个关键过程：受体泛素化和肌动蛋白细胞骨架的重塑。酪氨酸激酶在受体内吞作用和肌动蛋白重组中发挥关键作用。有趣的是，Abl 家族的成员是唯一已知的具有肌动蛋白结合域的酪氨酸激酶，因此具有直接调节肌动蛋白细胞骨架的潜力。然而，非转化性 cAbl 在受体内吞作用中的作用仍不清楚。我们报道 cAbl 促进 B 淋巴细胞中配体诱导的抗原受体内吞作用。我们发现，cAbl 的药理抑制或基因缺失会导致细胞骨架接头 CrkII 的酪氨酸磷酸化缺陷，cAbl 抑制或消除也会损害 CrkII 下游的 Rac 激活，以及抗原受体加帽和内吞作用。虽然 CrkII 的磷酸化被认为可以将其维持在封闭的非活性构象，但我们证明它实际上对于 Rac 的激活至关重要。另一方面。 CrkII 与 cCbl 的关联，cCbl 是受体泛素化的关键介质。不需要 CrkII 磷酸化并且不依赖于 cAbl。 cCbl 本身的磷酸化也是与 cAbl 无关的。因此，我们的结果表明，CrkII 通过耦合 cCbl 和 cAbl 介导的信号通路（协同调节配体诱导的受体内吞作用）将受体结合与细胞骨架重塑联系起来。 (C) 2009 Elsevier Inc. 保留所有权利。
There are two key processes underlying ligand-induced receptor endocytosis: receptor ubiquitylation and remodeling of the actin cytoskeleton. Tyrosine kinases play critical roles in both receptor endocytosis and actin reorganization. Interestingly, members of the Abl family are the only known tyrosine kinases that possess an actin-binding domain and thus have the potential to directly regulate the actin cytoskeleton. However, the role of non-transforming cAbl in receptor endocytosis remains undefined. We report that cAbl promotes ligand-induced antigen receptor endocytosis in B lymphocytes. We show that pharmacologic inhibition or genetic deletion of cAbl causes a defect in tyrosine phosphorylation of the cytoskeletal adapter CrkII cAbl inhibition or ablation also impairs Rac activation downstream of CrkII, as well as antigen receptor capping and endocytosis. Although phosphorylation of CrkII has been suggested to maintain it in a closed inactive conformation, we demonstrate that it is in fact essential for the activation of Rac. On the other hand. association of CrkII with cCbl, a key mediator of receptor ubiquitylation. does not require CrkII phosphorylation and is cAbl-independent. Phosphorylation of cCbl itself is also cAbl-independent. Our results thus indicate that CrkII links receptor engagement to cytoskeletal remodeling by coupling cCbl- and cAbl-mediated signaling pathways that cooperatively regulate ligand-induced receptor endocytosis. (C) 2009 Elsevier Inc. All rights reserved.