Mattagajasingh Subhendra N, Yang Xiao Ping, Irani Kaikobad, Mattagajasingh Ilwola, Becker Lewis C
Division of Cardiology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Biochim Biophys Acta. 2012 May;1823(5):997-1006. doi: 10.1016/j.bbamcr.2012.02.008.
Stat3 is an important transcription factor that regulates both proinflammatory and anit-apoptotic pathways in the heart. This study examined the mechanisms of activation of Stat3 in human endothelial cells following hypoxia/reoxygenation (H/R). By expression of constitutively active Rac1 mutant protein, and by RNA silencing of Rac1, we found that Stat3 forms a multiprotein complex with Rac1 and PKC in an H/R-dependent manner, which at least in part, appears to regulate Stat3 S727 phosphorylation. Selective inhibition of PKC with calphostin C produces a marked suppression of Stat3 S727 phosphorylation. The association of Stat3 with Rax1 occurs predominantly at the cell membrane, but also inside the nucleus, and occurs through the binding of the coiled-coil domain of Stat3 to the 54 NH(2)-terminal residues of Rac1. Transfection with a peptide comprising the NH(2)-terminal 17 amino acid residues of Rac1-dependent signaling pathways resulting in physical association between Rac1 and Stat3 and the formation of a novel multiprotein complex with PKC.
信号转导和转录激活因子3（Stat3）是一种重要的转录因子，可调节心脏中的促炎和抗凋亡途径。本研究探讨了缺氧/复氧（H/R）后人内皮细胞中Stat3的激活机制。通过组成型活性Rac1突变蛋白的表达以及Rac1的RNA沉默，我们发现Stat3以H/R依赖的方式与Rac1和蛋白激酶C（PKC）形成多蛋白复合物，这至少部分似乎调节Stat3 S727磷酸化。用钙磷蛋白C选择性抑制PKC可显著抑制Stat3 S727磷酸化。Stat3与Rax1的结合主要发生在细胞膜，但也发生在细胞核内，并且是通过Stat3的卷曲螺旋结构域与Rac1的54个NH(2)末端残基结合而发生的。用包含Rac1依赖信号通路的NH(2)末端17个氨基酸残基的肽进行转染，导致Rac1与Stat3之间发生物理结合，并与PKC形成新的多蛋白复合物。
