期刊
JOURNAL OF CELL SCIENCE
卷 124, 期 13, 页码 2153-2164出版社
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.078535
关键词
Lyn; Adhesion; Neutrophil chemotaxis; Rap1; CrkL
类别
资金
- NIH [GM083812, GM083601, HD059002]
- NSF [0953267]
- Direct For Biological Sciences
- Division Of Integrative Organismal Systems [953267] Funding Source: National Science Foundation
Establishing new adhesions at the extended leading edges of motile cells is essential for stable polarity and persistent motility. Despite recent identification of signaling pathways that mediate polarity and chemotaxis in neutrophils, little is known about molecular mechanisms governing cell-extracellular-matrix (ECM) adhesion in these highly polarized and rapidly migrating cells. Here, we describe a signaling pathway in neutrophils that is essential for localized integrin activation, leading edge attachment and persistent migration during chemotaxis. This pathway depends upon G(1)-protein-mediated activation and leading edge recruitment of Lyn, a nonreceptor tyrosine kinase belonging to the Src kinase family. We identified the small GTPase Rap1 as a major downstream effector of Lyn to regulate neutrophil adhesion during chemotaxis. Depletion of Lyn in neutrophil-like HL-60 cells prevented chemoattractant-induced Rap1 activation at the leading edge of the cell, whereas ectopic expression of Rap1 largely rescued the defects induced by Lyn depletion. Furthermore, Lyn controls spatial activation of Rap1 by recruiting the CrkL-C3G protein complex to the leading edge. Together, these results provide novel mechanistic insights into the poorly understood signaling network that controls leading edge adhesion during chemotaxis of neutrophils, and possibly other amoeboid cells.
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