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MAPK-induced Gab1 translocation to the plasma membrane depends on a regulated intramolecular switch

机译：MAPK诱导的Gab1易位至质膜取决于调节的分子内开关

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The timely orchestration of multiple signalling pathways is crucial for the integrity of an organism and therefore tightly controlled. Gab family proteins coordinate signal transduction at the plasma membrane (PM) by acting as docking platforms for signalling components involved in MAP kinase (MAPK), PI3 kinase (PI3K), phospholipase C (PLC) and Rho family GTPase signalling. The interaction with these components as well as the targeting of the docicing platform to the PM underlies complex spatial and temporal regulatory mechanisms. Deregulated Gab1 activation and membrane binding have been observed in some haematopoietic malignancies and solid tumours, thereby contributing, for example, to the development of Philadelphia chromosome-negative myeloproliferative neoplasms and certain lung cancers. Previously, we could demonstrate that the presence of PIP3 in the PM, which is increased in many cancer cells, is not sufficient for constitutive Gab1 membrane recruitment. In addition, MAPK-dependent phosphorylation of Gab1 at serine 552 (Ser552) is vital for Gab1 membrane binding. Here, we confirm our hypothesis that in the absence of MAPK activity an intrinsic part of Gab1 prevents binding to PIP3 at the PM. This epitope of Gab1, which encompasses Ser552, interacts directly with the Gab1 PH domain. Two arginines located in positions +4 and +8 of Ser552 are essential for the interaction with the PH domain, as well as for the inhibition of membrane recruitment of unphosphorylated Gab1. Ser552 phosphorylation is dispensable in respective arginine to alanine mutants of Gab1. Gab1 recruitment to the PM is highly dynamic and continuous PI3K and MAPK activities are both essential for sustained Gab1 membrane localisation. Our data document the existence of a sophisticated and robust control mechanism that prevents Gab1 translocation and signalling complex assembly after the activation of either MAPK or PI3K alone. (C) 2014 Elsevier Inc All rights reserved.
机译：多种信号通路的及时协调对于有机体的完整性至关重要，因此受到严格控制。 Gab家族蛋白通过充当与MAP激酶（MAPK），PI3激酶（PI3K），磷脂酶C（PLC）和Rho家族GTPase信号传导有关的信号传导平台的对接平台，协调质膜（PM）处的信号转导。与这些组件的交互以及将配药平台定位到PM，是复杂的时空调节机制的基础。在某些造血系统恶性肿瘤和实体瘤中已观察到Gab1激活失控和膜结合，从而促进了例如费城染色体阴性骨髓增生性肿瘤和某些肺癌的发生。以前，我们可以证明PIP3在PM中的存在（在许多癌细胞中增加）不足以组成性Gab1膜募集。此外，丝氨酸552（Ser552）上Gab1的MAPK依赖性磷酸化对于Gab1膜结合至关重要。在这里，我们证实了这样的假设：在没有MAPK活性的情况下，Gab1的固有部分会阻止在PM处与PIP3结合。 Gab1的这个表位（包含Ser552）直接与Gab1 PH域相互作用。位于Ser552的+4和+8位置的两个精氨酸对于与PH结构域的相互作用以及抑制未磷酸化的Gab1的膜募集至关重要。在相应的精氨酸中，Ser552磷酸化是Gab1的丙氨酸突变体。 Gab1募集到PM是高度动态的，连续的PI3K和MAPK活动对于持续的Gab1膜定位都是必不可少的。我们的数据记录了复杂而强大的控制机制的存在，该机制可防止仅激活MAPK或PI3K后Gab1易位并发出复杂的信号。 （C）2014 Elsevier Inc保留所有权利。

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