title: The non-receptor tyrosine kinase Lyn controls neutrophil adhesion by recruiting the CrkL-C3G complex and activating Rap1 at the leading edge.
abstract: 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(i)-protein-mediated activation and leading edge recruitment of Lyn, a non-receptor 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.
authors.affiliation: Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: He
authors.forename: Ashish
authors.initials: A
authors.lastname: Kapoor
authors.forename: Sara
authors.initials: S
authors.lastname: Cook
authors.forename: Shubai
authors.initials: S
authors.lastname: Liu
authors.forename: Yang
authors.initials: Y
authors.lastname: Xiang
authors.forename: Christopher V
authors.initials: CV
authors.lastname: Rao
authors.forename: Paul J A
authors.initials: PJ
authors.lastname: Kenis
authors.forename: Fei
authors.initials: F
authors.lastname: Wang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology*; D002460:Cell Line; D002465:Cell Movement; D002633:Chemotaxis / Q000502:physiology; D005109:Extracellular Matrix / Q000378:metabolism; D020735:Guanine Nucleotide-Releasing Factor 2 / Q000378:metabolism*; D006801:Humans; D009504:Neutrophils / Q000166:cytology* / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D011485:Protein Binding; D000089804:Shelterin Complex; D015398:Signal Transduction; D034501:Telomere-Binding Proteins / Q000378:metabolism*; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C082869:CRKL protein; D020735:Guanine Nucleotide-Releasing Factor 2; D009687:Nuclear Proteins; D000089804:Shelterin Complex; C440809:TERF2IP protein, human; D034501:Telomere-Binding Proteins; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases