Denofrio Jan C, Yuan Weiping, Temple Brenda R, Gentry Holly R, Parise Leslie V
Curriculum in Genetics and Molecular Biology, The University of North Carolina, Chapel Hill, NC 27599, USA.
Thromb Haemost. 2008 Nov;100(5):847-56.
Platelet aggregation requires activation of the alphaIIbbeta3 integrin, an event regulated by the integrin cytoplasmic tails. CIB1 binds to the cytoplasmic tail of the integrin alphaIIb subunit. Previous over-expression and knockdown studies in murine megakaryocytes demonstrated that CIB1 inhibits integrin alphaIIbbeta3 activation. Here we analyzed Cib1(-/-) mice to determine the function of CIB1 in platelets in vitro and in vivo. We found that although these mice had no overt platelet phenotype, mRNA level of CIB1 homolog CIB3 was increased in Cib1(-/-) megakaryocytes. In vitro binding experiments showed that recombinant CIB1, -2 and -3 bound specifically to an alphaIIb cytoplasmic tail peptide. Subsequent protein modeling experiments indicated that CIBs 1-3 each have a highly conserved hydrophobic binding pocket. Therefore, the potential exists for compensation for the loss of CIB1 by these CIB family members, thereby preventing pathologic thrombus formation in Cib1(-/-) mice.
血小板聚集需要激活αIIbβ3整合素，这一过程由整合素细胞质尾巴调控。CIB1与整合素αIIb亚基的细胞质尾巴结合。先前在小鼠巨核细胞中进行的过表达和敲低研究表明，CIB1抑制整合素αIIbβ3的激活。在此，我们分析了Cib1(-/-)小鼠，以确定CIB1在体外和体内血小板中的功能。我们发现，尽管这些小鼠没有明显的血小板表型，但Cib1(-/-)巨核细胞中CIB1同源物CIB3的mRNA水平有所增加。体外结合实验表明，重组CIB1、-2和-3特异性结合αIIb细胞质尾巴肽。随后的蛋白质建模实验表明，CIBs 1-3各自具有高度保守的疏水结合口袋。因此，这些CIB家族成员有可能补偿CIB1的缺失，从而防止Cib1(-/-)小鼠形成病理性血栓。
