期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 114, 期 10, 页码 2693-2698出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1612900114
关键词
Rap1; adhesion; T cells; PLC epsilon 1; SDF-1 alpha
资金
- Irma T. Hirschl Trust
- Colton family
- Rheumatology Research Foundation
- NIH [2T32HL007151-36, R01AI125640]
Regulation of integrins is critical for lymphocyte adhesion to endothelium and migration throughout the body. Inside-out signaling to integrins is mediated by the small GTPase Ras-proximate-1 (Rap1). Using an RNA-mediated interference screen, we identified phospholipase C epsilon 1 (PLC epsilon 1) as a crucial regulator of stromal cell-derived factor 1 alpha (SDF-1 alpha)-induced Rap1 activation. We have shown that SDF-1 alpha-induced activation of Rap1 is transient in comparison with the sustained level following cross-linking of the antigen receptor. We identified that PLC epsilon 1 was necessary for SDF-1 alpha-induced adhesion using shear stress, cell morphology alterations, and crawling on intercellular adhesion molecule 1 (ICAM-1)-expressing cells. Structure-function experiments to separate the dual-enzymatic function of PLC epsilon 1 uncover necessary contributions of the CDC25, Pleckstrin homology, and Ras-associating domains, but not phospholipase activity, to this pathway. In the mouse model of delayed type hypersensitivity, we have shown an essential role for PLC epsilon 1 in T-cell migration to inflamed skin, but not for cytokine secretion and proliferation in regional lymph nodes. Our results reveal a signaling pathway where SDF-1 alpha induces T-cell adhesion through activation of PLC epsilon 1, suggesting that PLC epsilon 1 is a specific potential target in treating conditions involving migration of T cells to inflamed organs.
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