Competition for talin results in trans-dominant inhibition of integrin activation
Competition for talin results in trans-dominant inhibition of integrin activation
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DOI：
10.1074/jbc.m402161200
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发表时间：
2004-07-09
影响因子：
4.8
通讯作者：
Ginsberg, MH
中科院分区：
文献类型：
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作者：
Calderwood, DA;Tai, V;Ginsberg, MH
整合素粘附受体对其胞外配体的亲和力发生快速变化（整合素激活）的能力对于多细胞动物的发育和功能至关重要，并且取决于整合素β亚基胞质尾部和细胞骨架蛋白talin之间的相互作用。不同整合素之间以及整合素与其他受体之间的串扰影响许多细胞过程，包括粘附、扩散、迁移、凝块收缩、增殖和分化。当配体与一个整合素结合抑制第二个整合素的激活时，就会发生整合素串扰的一种形式，即整合素激活的跨显性抑制。这可能在许多情况下具有临床相关性，例如血小板粘附、白细胞迁移和血管生成期间。在这里，我们报道了对talin的竞争是整合素激活的反式显性抑制的基础。这一结论基于我们的观察：(i) 踝蛋白结合选择性缺陷的 β 尾不能介导反式显性抑制，(ii) 反式显性抑制可以通过整合素结合和激活踝蛋白片段的过度表达来逆转，以及 (iii) 另一种非整联蛋白踝蛋白结合蛋白（磷脂酰肌醇磷酸激酶 Igamma-90 型）的表达也抑制整合素激活。因此，抑制性物种对踝蛋白的隔离对于整联蛋白激活的反式显性抑制是必要且充分的。
The ability of integrin adhesion receptors to undergo rapid changes in affinity for their extracellular ligands ( integrin activation) is essential for the development and function of multicellular animals and is dependent on interactions between the integrin beta subunit-cytoplasmic tail and the cytoskeletal protein talin. Cross-talk among different integrins and between integrins and other receptors impacts many cellular processes including adhesion, spreading, migration, clot retraction, proliferation, and differentiation. One form of integrin cross-talk, transdominant inhibition of integrin activation, occurs when ligand binding to one integrin inhibits the activation of a second integrin. This may be relevant clinically in a number of settings such as during platelet adhesion, leukocyte trans-migration, and angiogenesis. Here we report that competition for talin underlies the trans-dominant inhibition of integrin activation. This conclusion is based on our observations that ( i) beta tails selectively defective in talin binding are unable to mediate trans-dominant inhibition, (ii) trans-dominant inhibition can be reversed by overexpression of integrin binding and activating fragments of talin, and (iii) expression of another non-integrin talin-binding protein, phosphatidylinositol phosphate kinase type Igamma-90, also inhibits integrin activation. Thus, the sequestration of talin by the suppressive species is both necessary and sufficient for trans-dominant inhibition of integrin activation.