Focal adhesion kinase family is involved in matrix contraction by transdifferentiated Muller cells
Focal adhesion kinase family is involved in matrix contraction by transdifferentiated Muller cells
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DOI：
10.1016/j.exer.2017.08.010
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发表时间：
2017-11-01
影响因子：
3.4
通讯作者：
Tamiya, Shigeo
中科院分区：
文献类型：
--
作者：
Tsukahara, Rintaro;Umazume, Kazuhiko;Tamiya, Shigeo
采用成纤维细胞/肌成纤维细胞表型的转分化Muller细胞已在几种眼部疾病的视网膜前膜（ERMs）中被发现，并在ERMs的形成和/或收缩中发挥作用。我们之前已经证明，dasatinib是src家族激酶和Abl激酶的双重抑制剂，可以阻止转分化Muller细胞的基质收缩。在这项研究中，我们检查了参与达沙替尼主要靶点下游基质收缩的分子。达沙替尼显著降低了FAK家族成员FAK和PYK2的酪氨酸磷酸化，这些激酶的抑制剂PF431396（同时抑制FAR和PYK2）和PF573228（仅抑制FAR而不抑制PYK2）显著降低了转分化Muller细胞的基质收缩。达沙替尼和PF431396显著降低Hic-5的磷酸化，Hic-5是一种参与局灶黏附和细胞信号传导的蛋白。我们的数据显示FAK家族成员参与转分化Muller细胞的基质收缩，也暗示Hic-5在信号通路中位于FAK家族的下游。(C) 2017 Elsevier Ltd.版权所有。
Transdifferentiated Muller cells that adopt a fibroblastic/myofibroblastic phenotype have been identified in epiretinal membranes (ERMs) in several ocular disorders, and have been implicated to play a role in the formation and/or the contraction of ERMs. We have previously demonstrated that dasatinib, a dual inhibitor of Src-family kinases and Abl kinase, can prevent matrix contraction by transdifferentiated Muller cells. In this study, we examined molecules involved in matrix contraction downstream of primary dasatinib targets. Tyrosine phosphorylation of focal adhesion kinase (FAK) family members FAK and PYK2 was significantly reduced by dasatinib, and select inhibitors for these kinases PF431396, which inhibits both FAR and PYK2, and PF573228, which only inhibits FAR and not PYK2, significantly reduced matrix contraction by transdifferentiated Muller cells. Dasatinib and PF431396 significantly reduced phosphorylation of Hic-5, a protein implicated to play a role in focal adhesions and cell signaling. Our data shows that FAK family members are involved in matrix contraction by transdifferentiated Muller cells, and also implicates that Hic-5 is situated downstream of the FAK family within the signaling pathway. (C) 2017 Elsevier Ltd. All rights reserved.