Phospholipase Cγ2 modulates integrin signaling in the osteoclast by affecting the localization and activation of Src kinase
Phospholipase Cγ2 modulates integrin signaling in the osteoclast by affecting the localization and activation of Src kinase
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DOI：
10.1128/mcb.00259-08
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发表时间：
2008-06-01
影响因子：
5.3
通讯作者：
Faccio, Roberta
中科院分区：
文献类型：
--
作者：
Epple, Holly;Cremasco, Viviana;Faccio, Roberta
整合素参与诱导级联信号传导途径，包括导致肌动蛋白细胞骨架调节的许多蛋白质的酪氨酸磷酸化。Src是整合素依赖性功能的主要细胞内介质，但是Src响应于整合素信号而被调节的机制尚未完全理解。在这里，我们证明了磷脂酶C γ 2（PLC γ 2）在Src激活破骨细胞中的重要作用。通过对PLC γ 2（-/-）小鼠的原代细胞的分析，发现PLC γ 2是α（v）β（3）整联蛋白介导的骨破骨细胞粘附、迁移和骨吸收的重要调节剂。在PLC γ 2不存在的情况下，粘附诱导的PYK 2和Src磷酸化降低，并且Src与β（3）整联蛋白和PYK 2的相互作用显著降低。重要的是，PLC γ 2被认为是需要适当的本地化Src的密封肌动蛋白环，这一功能需要其催化活性和衔接域。基于这些结果，我们提出PLC γ 2通过介导Src定位于整合素复合物从而调节破骨细胞中整合素介导的功能来影响Src活化。
Integrin engagement induces a cascade of signaling pathways that include tyrosine phosphorylation of numerous proteins that lead to modulation of the actin cytoskeleton. Src is a major intracellular mediator of integrin-dependent functions, but the mechanism(s) by which Src is regulated in response to integrin signals is not fully understood. Here, we demonstrate an important role for phospholipase C gamma 2 (PLC gamma 2) in Src activation in the osteoclast. Through analysis of primary cells from PLC gamma 2(-/-) mice, PLC gamma 2 was found to be an important regulator of alpha(v)beta(3) integrin-mediated bone osteoclast cell adhesion, migration, and bone resorption. Adhesion-induced PYK2 and Src phosphoryllation is decreased in the absence of PLC gamma 2, and the interaction of Src with beta(3) integrin and PYK2 is dramatically reduced. Importantly, PLC gamma 2 was found to be required for proper localization of Src to the sealing actin ring, and this function required both its catalytic activity and adapter domains. Based on these results, we propose that PLC gamma 2 influences Src activation by mediating the localization of Src to the integrin complex and thereby regulating integrin-mediated functions in the osteoclast.