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Beta-arrestins operate an on/off control switch for focal adhesion kinase activity.
Cellular and Molecular Life Sciences ( IF 8 ) Pub Date : 2020-02-10 , DOI: 10.1007/s00018-020-03471-5
Revu Ann Alexander 1 , Isaure Lot 1 , Kusumika Saha 1 , Guillaume Abadie 1 , Mireille Lambert 1 , Eleonore Decosta 1 , Hiroyuki Kobayashi 2 , Alexandre Beautrait 2 , Aurélie Borrull 1 , Atef Asnacios 3 , Michel Bouvier 2 , Mark G H Scott 1 , Stefano Marullo 1 , Hervé Enslen 1
Affiliation  

Focal adhesion kinase (FAK) regulates key biological processes downstream of G protein-coupled receptors (GPCRs) in normal and cancer cells, but the modes of kinase activation by these receptors remain unclear. We report that after GPCR stimulation, FAK activation is controlled by a sequence of events depending on the scaffolding proteins β-arrestins and G proteins. Depletion of β-arrestins results in a marked increase in FAK autophosphorylation and focal adhesion number. We demonstrate that β-arrestins interact directly with FAK and inhibit its autophosphorylation in resting cells. Both FAK–β-arrestin interaction and FAK inhibition require the FERM domain of FAK. Following the stimulation of the angiotensin receptor AT1AR and subsequent translocation of the FAK–β-arrestin complex to the plasma membrane, β-arrestin interaction with the adaptor AP-2 releases inactive FAK from the inhibitory complex, allowing its activation by receptor-stimulated G proteins and activation of downstream FAK effectors. Release and activation of FAK in response to angiotensin are prevented by an AP-2-binding deficient β-arrestin and by a specific inhibitor of β-arrestin/AP-2 interaction; this inhibitor also prevents FAK activation in response to vasopressin. This previously unrecognized mechanism of FAK regulation involving a dual role of β-arrestins, which inhibit FAK in resting cells while driving its activation at the plasma membrane by GPCR-stimulated G proteins, opens new potential therapeutic perspectives in cancers with up-regulated FAK.



中文翻译:

β-arrestins可通过开关控制粘着斑激酶活性。

黏着斑激酶(FAK)调节正常和癌细胞中G蛋白偶联受体(GPCR)下游的关键生物学过程,但这些受体激活激酶的方式仍不清楚。我们报告说,在GPCR刺激后,FAK激活受一系列事件的控制,这些事件取决于支架蛋白β-arrestins和G蛋白。β-arrestins的耗尽会导致FAK自磷酸化和粘着斑数目显着增加。我们证明,β-arrestins与FAK直接相互作用并抑制其在静息细胞中的自磷酸化。FAK-β-arrestin相互作用和FAK抑制都需要FAK的FERM域。在刺激血管紧张素受体AT 1A之后R和随后的FAK-β-arrestin复合物向质膜的转运,β-arrestin与衔接子AP-2的相互作用释放了抑制性复合物中的非活性FAK,从而使其被受体刺激的G蛋白激活并激活了下游FAK效应子。AP-2-结合缺陷型β-arrestin和β-arrestin/ AP-2相互作用的特异性抑制剂可阻止FAK响应血管紧张素的释放和活化。该抑制剂还可以防止血管加压素引起的FAK活化。FAK调控的这种先前未被认识的机制涉及β-arrestin的双重作用,它抑制静止细胞中的FAK,同时通过GPCR刺激的G蛋白驱动其在质膜上的活化,为FAK上调的癌症开辟了新的潜在治疗前景。

更新日期:2020-02-10
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