title: The integrin LFA-1 signals through ZAP-70 to regulate expression of high-affinity LFA-1 on T lymphocytes.
abstract: The integrin lymphocyte function-associated antigen 1 (LFA-1) controls many functions of T lymphocytes and is particularly essential during lymphocyte migration from blood into tissues. LFA-1 is considered to initiate "outside-in" signaling when bound to ligand intercellular adhesion molecule 1 (ICAM-1), but little is known about the proteins involved or where in the cell such LFA-1-mediated signaling might be operating. Here we show that LFA-1 is constitutively associated with the protein tyrosine kinases Lck and zeta chain-associated protein of 70 kDa (ZAP-70). When LFA-1 binds ICAM-1, both kinases become phosphorylated and the consequence of kinase activation is the conversion of intermediate- to high-affinity LFA-1 and an increase in close contact with ICAM-1. In the polarized T lymphocyte, phospho-ZAP-70 is concentrated within a region of high-affinity LFA-1 that includes talin and encompasses the lamella/lamellipodial interface as well as further back in the cell. Deficiency of ZAP-70 through inhibition or knockdown in T lymphocytes decreases the speed of migration on ICAM-1, as well as reducing firm adhesion under shear-flow conditions. Through its control of high-affinity LFA-1, the LFA-1/Lck/ZAP-70 complex is in position to initiate the rapid adhesion strengthening and migration necessary for T-lymphocyte responses when stimulated vasculature is encountered at sites of infection or injury.
authors.affiliation: Leukocyte Adhesion Laboratory, Cancer Research UK London Research Institute, London, United Kingdom.
authors.forename: Rachel
authors.initials: R
authors.lastname: Evans
authors.forename: Annemarie C
authors.initials: AC
authors.lastname: Lellouch
authors.forename: Lena
authors.initials: L
authors.lastname: Svensson
authors.forename: Alison
authors.initials: A
authors.lastname: McDowall
authors.forename: Nancy
authors.initials: N
authors.lastname: Hogg
mesh_terms: D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000235:genetics / Q000276:immunology / Q000502:physiology; D006801:Humans; D016023:Integrins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics; D016169:Lymphocyte Function-Associated Antigen-1 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism / Q000502:physiology; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013379:Substrate Specificity; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D014162:Transfection; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D016023:Integrins; D016169:Lymphocyte Function-Associated Antigen-1; D034741:RNA, Small Interfering; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D051746:ZAP-70 Protein-Tyrosine Kinase