Draheim Kyle M, Huet-Calderwood Clotilde, Simon Bertrand, Calderwood David A
From the Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520.
From the Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520; the Department of Cell Biology, Yale University School of Medicine, New Haven, Connecticut 06520.
J Biol Chem. 2017 Feb 3;292(5):1884-1898. doi: 10.1074/jbc.M116.762393. Epub 2016 Dec 21.
Binding of ICAP1 (integrin cytoplasmic domain-associated protein-1) to the cytoplasmic tails of β1 integrins inhibits integrin activation. ICAP1 also binds to KRIT1 (Krev interaction trapped-1), a protein whose loss of function leads to cerebral cavernous malformation, a cerebrovascular dysplasia occurring in up to 0.5% of the population. We previously showed that KRIT1 functions as a switch for β1 integrin activation by antagonizing ICAP1-mediated inhibition of integrin activation. Here we use overexpression studies, mutagenesis, and flow cytometry to show that ICAP1 contains a functional nuclear localization signal and that nuclear localization impairs the ability of ICAP1 to suppress integrin activation. Moreover, we find that ICAP1 drives the nuclear localization of KRIT1 in a manner dependent upon a direct ICAP1/KRIT1 interaction. Thus, nuclear-cytoplasmic shuttling of ICAP1 influences both integrin activation and KRIT1 localization, presumably impacting nuclear functions of KRIT1.
ICAP1（整合素胞质结构域相关蛋白-1）与β1整合素的胞质尾部结合会抑制整合素激活。ICAP1还与KRIT1（Krev相互作用捕获蛋白-1）结合，KRIT1功能缺失会导致脑海绵状血管畸形，这是一种在高达0.5%的人群中发生的脑血管发育异常。我们之前表明，KRIT1通过拮抗ICAP1介导的整合素激活抑制作用，作为β1整合素激活的开关。在这里，我们使用过表达研究、诱变和流式细胞术表明，ICAP1含有一个功能性核定位信号，并且核定位会损害ICAP1抑制整合素激活的能力。此外，我们发现ICAP1以依赖于直接ICAP1/KRIT1相互作用的方式驱动KRIT1的核定位。因此，ICAP1的核质穿梭影响整合素激活和KRIT1定位，推测会影响KRIT1的核功能。
