MERTK tyrosine kinase receptor together with TIM4 phosphatidylserine receptor mediates distinct signal transduction pathways for efferocytosis and cell proliferation
MERTK tyrosine kinase receptor together with TIM4 phosphatidylserine receptor mediates distinct signal transduction pathways for efferocytosis and cell proliferation
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DOI：
10.1074/jbc.ra118.006628
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发表时间：
2019-05-03
影响因子：
4.8
通讯作者：
Nagata, Shigekazu
中科院分区：
文献类型：
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作者：
Nishi, Chihiro;Yanagihashi, Yuichi;Nagata, Shigekazu
凋亡细胞在其表面上暴露磷脂酰丝氨酸（PtdSer），导致巨噬细胞增多，即它们被表达PtdSer受体T细胞免疫球蛋白粘蛋白受体4（TIM 4）和TAM家族受体酪氨酸激酶受体（MERTK、AXL和TYRO 3）的驻留巨噬细胞吞噬。TAM家族受体刺激细胞增殖，并且TAM家族受体下游的生长信号传导途径的许多方面先前已经阐明。然而，TAM受体介导的胞浆细胞增多症的信号级联一直是难以捉摸的。在这里，我们观察到，小鼠驻留的腹腔巨噬细胞的吞噬作用被MERTK、促分裂原活化蛋白激酶/细胞外信号调节激酶激酶（MEK）、AKT Ser/Thr激酶（AKT）、粘着斑激酶（FAK）或STAT 6通路的抑制剂阻断。因此，凋亡细胞刺激MERTK、ERK、AKT、FAK和STAT 6的磷酸化，但不刺激IB或STAT 5的磷酸化。使用表达MERTK和TIM 4的NIH 3 T3衍生细胞重建的红细胞增多系统显示MERTK的质膜和C末端区域在红细胞增多中具有冗余作用。用MERTK和TIM 4转化鼠IL-3依赖性Ba/F3细胞（一种前B细胞系），使其能够以PtdSer依赖性方式响应凋亡细胞增殖。这种凋亡细胞诱导的MERTK介导的增殖需要MERTK的质膜和C-末端区域，并且不仅被ERK、AKT、FAK和STAT 6的抑制剂阻断，而且被NF-B和STAT 5信号传导的抑制剂阻断。这些结果表明，凋亡细胞通过MERTK刺激不同的信号转导途径组，以诱导红细胞增多或增殖。
Apoptotic cells expose phosphatidylserine (PtdSer) on their surface, leading to efferocytosis, i.e. their engulfment by resident macrophages that express the PtdSer receptor T cell immunoglobulin mucin receptor 4 (TIM4) and TAM family receptor tyrosine kinase receptors (MERTK, AXL, and TYRO3). TAM family receptors stimulate cell proliferation, and the many aspects of the growth signaling pathway downstream of TAM family receptors have been elucidated previously. However, the signaling cascade for TAM receptor-mediated efferocytosis has been elusive. Here we observed that efferocytosis by mouse-resident peritoneal macrophages was blocked by inhibitors against the MERTK, mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK), AKT Ser/Thr kinase (AKT), focal adhesion kinase (FAK), or STAT6 pathway. Accordingly, apoptotic cells stimulated the phosphorylation of MERTK, ERK, AKT, FAK, and STAT6, but not of IB or STAT5. A reconstituted efferocytosis system using MERTK- and TIM4-expressing NIH3T3-derived cells revealed that the juxtamembrane and C-terminal regions of MERTK have redundant roles in efferocytosis. The transformation of murine IL-3-dependent Ba/F3 cells (a pro-B cell line) with MERTK and TIM4 enabled them to proliferate in response to apoptotic cells in a PtdSer-dependent manner. This apoptotic cell-induced MERTK-mediated proliferation required both MERTK's juxtamembrane and C-terminal regions and was blocked by inhibitors of not only ERK, AKT, FAK, and STAT6 but also of NF-B and STAT5 signaling. These results suggest that apoptotic cells stimulate distinct sets of signal transduction pathways via MERTK to induce either efferocytosis or proliferation.