Distinct roles for the α , β and γ1 isoforms of protein phosphatase 1 in the outside-in αIIbβ3 integrin signalling-dependent functions.
Distinct roles for the α , β and γ1 isoforms of protein phosphatase 1 in the outside-in αIIbβ3 integrin signalling-dependent functions.
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DOI：
10.1160/th12-04-0237
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发表时间：
2013-01
影响因子：
6.7
通讯作者：
Vijayan KV
中科院分区：
文献类型：
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作者：
Alrehani N;Pradhan S;Khatlani T;Kailasam L;Vijayan KV
虽然蛋白激酶和磷酸酶参与整合素αIIbβ3信号传导，但整合素功能是否受蛋白磷酸酶1（PP1c）异构体催化亚基的调节尚不清楚。我们发现，siRNA介导的293 αIIbβ3细胞中所有PP1c亚型（α、β和γ1）的敲低降低了对固定纤维蛋白原的粘附和纤维蛋白凝块的收缩。仅选择性敲除PP1cγ1并不改变粘附或凝块收缩，而PP1cβ的缺失则降低了这两种功能。出乎意料的是，PP1cα的敲低增强了αIIbβ3与纤维蛋白原的粘附和血块收缩。蛋白质相互作用的研究表明，所有的PP1c异构体可以与整合素αIIb亚基相互作用。磷酸化分析显示，在PP1cα缺失的细胞中，促分裂原活化蛋白激酶（MAPK）p38的活化增强。PP1cα缺失的293 αIIbβ3细胞显示的粘附表型增强可通过p38的药理学抑制作用阻断。相反，PP1cα过表达细胞的粘附性下降被组成性活性p38α或p38γ的表达所挽救。因此，PP1c亚型对293 αIIbβ3细胞中由外向内的αIIbβ3信号传导依赖性功能具有明显的贡献。此外，PP1cα通过抑制p38通路负调节整合素功能。
Although protein kinases and phosphatases participate in integrin αIIbβ3 signaling, whether integrin functions are regulated by the catalytic subunit of protein phosphatase 1 (PP1c) isoforms are unclear. We show that siRNA mediated knockdown of all PP1c isoforms (α, β and γ1) in 293 αIIbβ3 cells decreased adhesion to immobilized fibrinogen and fibrin clot retraction. Selective knockdown of only PP1cγ1 did not alter adhesion or clot retraction, while depletion of PP1cβ decreased both functions. Unexpectedly, knockdown of PP1cα enhanced αIIbβ3 adhesion to fibrinogen and clot retraction. Protein interaction studies revealed that all PP1c isoforms can interact with the integrin αIIb subunit. Phosphoprofiling studies revealed an enhanced activation of mitogen-activated protein kinase (MAPK) p38 in the PP1cα depleted cells. Enhanced adhesive phenotype displayed by the PP1cα depleted 293 αIIbβ3 cells was blocked by pharmacological inhibition of p38. Conversely, the decreased adhesion of PP1cα overexpressing cells was rescued by the expression of constitutively active p38α or p38γ. Thus, PP1c isoforms have distinct contribution to the outside-in αIIbβ3 signaling-dependent functions in 293 αIIbβ3 cells. Moreover, PP1cα negatively regulates integrin function by suppressing the p38 pathway.