Syk-mediated translocation of PI3Kdelta to the leading edge controls lamellipodium formation and migration of leukocytes.
Syk-mediated translocation of PI3Kdelta to the leading edge controls lamellipodium formation and migration of leukocytes.
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Syk介导的PI3KDELTA转移到前缘控制的层状叶片和白细胞的迁移。
DOI：
10.1371/journal.pone.0001132
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发表时间：
2007-11-07
期刊：
影响因子：
3.7
通讯作者：
Walzog, Barbara
中科院分区：
文献类型：
--
作者：
Schymeinsky, Juergen;Then, Cornelia;Sindrilaru, Anca;Gerstl, Ronald;Jakus, Zoltan;Tybulewicz, Victor L. J.;Scharffetter-Kochanek, Karin;Walzog, Barbara
非受体酪氨酸激酶Syk主要在造血系统中表达，在β2整合素介导的白细胞活化中起重要作用。阐明β2整合素介导的Syk下游信号通路（CD 11/CD 18）介导的多形核中性粒细胞（PMN）迁移和外渗，我们产生了嗜中性粒细胞样分化的HL-60（dHL-60）细胞，该细胞表达荧光标记的Syk突变体，该突变体在323位缺少酪氨酸残基已知结合IA类磷脂酰肌醇3-激酶（PI 3 K）的调节亚基p85所需的Syk-Tyr 323。发现Syk-Tyr 323对于富集IA类PI 3 K的催化亚基p110δ以及在大多数极化细胞的前缘产生PI 3 K产物是关键的。相应地，在Syk缺陷的小鼠PMN中，PI 3 K p110δ向前缘的移位减少。此外，EGFP-Syk Y323 F的表达干扰了细胞的正常极化，并损害了dHL-60细胞的有效迁移。与β2整合素在吞噬细胞募集至病变部位中的主要作用一致，Syk缺陷型造血系统小鼠表现出受损的PMN浸润至创伤组织中，这与皮肤创伤愈合时间延长相关。这些数据表明Syk通过PI 3 K p110δ信号传导在β2整合素介导的迁移中发挥新的作用，这是体内有效的PMN募集的先决条件。
The non-receptor tyrosine kinase Syk is mainly expressed in the hematopoietic system and plays an essential role in β2 integrin-mediated leukocyte activation. To elucidate the signaling pathway downstream of Syk during β2 integrin (CD11/CD18)-mediated migration and extravasation of polymorphonuclear neutrophils (PMN), we generated neutrophil-like differentiated HL-60 (dHL-60) cells expressing a fluorescently tagged Syk mutant lacking the tyrosine residue at the position 323 (Syk-Tyr323) that is known to be required for the binding of the regulatory subunit p85 of the phosphatidylinositol 3-kinase (PI3K) class IA. Syk-Tyr323 was found to be critical for the enrichment of the catalytic subunit p110δ of PI3K class IA as well as for the generation of PI3K products at the leading edge of the majority of polarized cells. In accordance, the translocation of PI3K p110δ to the leading edge was diminished in Syk deficient murine PMN. Moreover, the expression of EGFP-Syk Y323F interfered with proper cell polarization and it impaired efficient migration of dHL-60 cells. In agreement with a major role of β2 integrins in the recruitment of phagocytic cells to sites of lesion, mice with a Syk-deficient hematopoietic system demonstrated impaired PMN infiltration into the wounded tissue that was associated with prolonged cutaneous wound healing. These data imply a novel role of Syk via PI3K p110δ signaling for β2 integrin-mediated migration which is a prerequisite for efficient PMN recruitment in vivo.
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