期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 294, 期 18, 页码 7221-7230出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA118.006628
关键词
apoptosis; macrophage; signal transduction; phosphatidylserine; phosphorylation; cell death; cell signaling; cancer; efferocytosis; kinase
资金
- Japan Society for the Promotion of Science (JSPS) [16H06943]
- JSPS [15H05785]
- Japan Science and Technology Agency [JPMJCR14M4]
- Grants-in-Aid for Scientific Research [15H05785, 16H06943] Funding Source: KAKEN
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据