A role for Mer tyrosine kinase in αvβ5 integrin-mediated phagocytosis of apoptotic cells
A role for Mer tyrosine kinase in αvβ5 integrin-mediated phagocytosis of apoptotic cells
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DOI：
10.1242/jcs.01632
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发表时间：
2005-02-01
影响因子：
4
通讯作者：
Birge, RB
中科院分区：
文献类型：
--
作者：
Wu, Y;Singh, S;Birge, RB
凋亡细胞的有效吞噬对于许多细胞过程是至关重要的。吞噬细胞最早的信号之一是凋亡细胞外表面磷脂酰丝氨酸（PS）的表达，它提供了一个有效的“吃我”信号。通过PS受体（PS-R）直接识别PS，或通过α v β 5（3）整联蛋白或Mer家族酪氨酸激酶分别通过调理蛋白乳脂肪球-EGF因子8蛋白（MFG-E8）或生长停滞特异性因子-6（Gas 6）间接识别PS。因为Mer和α v β 5整合素共享PS依赖性识别信号，我们研究了它们在受体活化后的受体后信号级联。使用Mer的组成型活性形式（CDMer）或Gas 6作为刺激Mer的配体，我们发现Mer激活诱导了一个受体后信号级联反应，涉及Src介导的Tyr（861）上FAK的酪氨酸磷酸化，FAK（Tyr 861）向α v β 5整联蛋白的募集，以及增加p130（CAS）/CrkII/Dock 180复合物的形成以激活Rac 1。Mer与α v β 5整合素的共表达对Rac 1活化、片状脂质体形成和凋亡细胞的吞噬作用具有协同作用。有趣的是，Gas 6或CDMer未能刺激β 5缺陷CS-1细胞或突变型β 5 DeltaC表达细胞中的p130（CAS）酪氨酸磷酸化或吞噬作用，这表明Mer与整联蛋白途径有方向性和功能性联系。目前的数据表明，在PS背景下识别凋亡细胞的受体在功能上相互作用，以放大细胞内信号，从而内化凋亡细胞。此外，我们的数据将另一个PS依赖信号链接到CrkII/Dock 180/Rac 1模块。
Efficient phagocytosis of apoptotic cells is crucial for many cellular processes. One of earliest signals to the phagocyte is the expression of phosphatidylserine (PS) on the outer surface of the apoptotic cell that provides a potent 'eat-me' signal. Recognition of PS occurs either directly, via PS receptor (PS-R), or indirectly via alphavbeta5(3) integrin or Mer-family tyrosine kinases through the opsonizing proteins milk fat globule-EGF factor 8 protein (MFG-E8), or growth arrest specific factor-6 (Gas6), respectively. Because Mer and alphavbeta5 integrin share PS-dependent recognition signals, we investigated their post-receptor signaling cascades following receptor activation. Using a constitutively active form for Mer (CDMer) or Gas6 as a ligand to stimulate Mer, we found that Mer activation induced a post-receptor signaling cascade involving Src-mediated tyrosine phosphorylation of FAK on Tyr(861), the recruitment of FAK(Tyr861) to the alphavbeta5 integrin, and increased formation of p130(CAS)/CrkII/Dock180 complex to activate Rac1. Coexpression of Mer with alphavbeta5 integrin had a synergistic effect on Rac1 activation, lamellipodial formation and the phagocytosis of apoptotic cells. Interestingly, Gas6 or CDMer failed to stimulate p130(CAS) tyrosine phosphorylation or phagocytosis in beta5-deficient CS-1 cells or in mutant beta5DeltaC-expressing cells, suggesting that Mer is directionally and functionally linked to the integrin pathway. The present data indicate that receptors that recognize apoptotic cells in the context of PS functionally crosstalk to amplify intracellular signals to internalize apoptotic cells. Moreover, our data link another PS-dependent signal to the CrkII/Dock180/Rac1 module.