Distinct biophysical mechanisms of focal adhesion kinase mechanoactivation by different extracellular matrix proteins
Distinct biophysical mechanisms of focal adhesion kinase mechanoactivation by different extracellular matrix proteins
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DOI：
10.1073/pnas.1307405110
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发表时间：
2013-11-26
影响因子：
11.1
通讯作者：
Wang, Yingxiao
中科院分区：
文献类型：
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作者：
Seong, Jihye;Tajik, Arash;Wang, Yingxiao
基质力学通过调节整合素和细胞外基质（ECM）蛋白之间的键来控制细胞命运。然而，目前尚不清楚纤连蛋白（FN），1型胶原蛋白，以及它们的受体整合素亚型如何明显地控制力的传递，以调节粘着斑激酶（FAK）的活性，一个重要的分子信号控制细胞粘附/迁移。在这里，我们表明，使用基因编码的FAK生物传感器的基础上的荧光共振能量转移，FN介导的FAK激活是依赖于机械张力，这可能会暴露其否则隐藏的FN协同位点整合素α 5。与此形成鲜明对比的是，1型胶原蛋白的组成性暴露的结合基序与其受体整合素α 2之间的连接令人惊讶地不依赖于张力以诱导足够的FAK活化。虽然整联蛋白α亚基决定机械敏感性，但α亚基与ECM蛋白之间的连接在整联蛋白β 1活化时会聚以诱导FAK活化。我们进一步发现，在细胞粘附过程中，N-末端蛋白4.1/ezrin/redixin/moesin碱性补丁与磷脂酰肌醇4，5-二磷酸的相互作用是至关重要的，以维持FAK活化，免受附近蛋白4.1/ezrin/redixin/moesin酸性位点的抑制作用。因此，不同的ECM蛋白可以传递或可以屏蔽机械力以调节细胞功能，其中ECM结合基序通过其特异性整合素α亚基的可接近性决定机械转导期间FAK活化的生物物理机制。
Matrix mechanics controls cell fate by modulating the bonds between integrins and extracellular matrix (ECM) proteins. However, it remains unclear how fibronectin (FN), type 1 collagen, and their receptor integrin subtypes distinctly control force transmission to regulate focal adhesion kinase (FAK) activity, a crucial molecular signal governing cell adhesion/migration. Here we showed, using a genetically encoded FAK biosensor based on fluorescence resonance energy transfer, that FN-mediated FAK activation is dependent on the mechanical tension, which may expose its otherwise hidden FN synergy site to integrin alpha 5. In sharp contrast, the ligation between the constitutively exposed binding motif of type 1 collagen and its receptor integrin alpha 2 was surprisingly tension-independent to induce sufficient FAK activation. Although integrin alpha subunit determines mechanosensitivity, the ligation between alpha subunit and the ECM proteins converges at the integrin beta 1 activation to induce FAK activation. We further discovered that the interaction of the N-terminal protein 4.1/ezrin/redixin/moesin basic patch with phosphatidylinositol 4,5-biphosphate is crucial during cell adhesion to maintain the FAK activation from the inhibitory effect of nearby protein 4.1/ezrin/redixin/moesin acidic sites. Therefore, different ECM proteins either can transmit or can shield from mechanical forces to regulate cellular functions, with the accessibility of ECM binding motifs by their specific integrin alpha subunits determining the biophysical mechanisms of FAK activation during mechanotransduction.