title: Kindlin-3 mediates integrin αLβ2 outside-in signaling, and it interacts with scaffold protein receptor for activated-C kinase 1 (RACK1).
abstract: Integrins are heterodimeric type I membrane cell adhesion molecules that are involved in many biological processes. Integrins are bidirectional signal transducers because their cytoplasmic tails are docking sites for cytoskeletal and signaling molecules. Kindlins are cytoplasmic molecules that mediate inside-out signaling and activation of the integrins. The three kindlin paralogs in humans are kindlin-1, -2, and -3. Each of these contains a 4.1-ezrin-radixin-moesin (FERM) domain and a pleckstrin homology domain. Kindlin-3 is expressed in platelets, hematopoietic cells, and endothelial cells. Here we show that kindlin-3 is involved in integrin αLβ2 outside-in signaling. It also promotes micro-clustering of integrin αLβ2. We provide evidence that kindlin-3 interacts with the receptor for activated-C kinase 1 (RACK1), a scaffold protein that folds into a seven-blade propeller. This interaction involves the pleckstrin homology domain of kindlin-3 and blades 5-7 of RACK1. Using the SKW3 human T lymphoma cells, we show that integrin αLβ2 engagement by its ligand ICAM-1 promotes the association of kindlin-3 with RACK1. We also show that kindlin-3 co-localizes with RACK1 in polarized SKW3 cells and human T lymphoblasts. Our findings suggest that kindlin-3 plays an important role in integrin αLβ2 outside-in signaling.
authors.affiliation: School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore.
authors.forename: Chen
authors.initials: C
authors.lastname: Feng
authors.forename: Yan-Feng
authors.initials: YF
authors.lastname: Li
authors.forename: Yin-Hoe
authors.initials: YH
authors.lastname: Yau
authors.forename: Hui-Shan
authors.initials: HS
authors.lastname: Lee
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Tang
authors.forename: Zhi-Hong
authors.initials: ZH
authors.lastname: Xue
authors.forename: Yi-Chao
authors.initials: YC
authors.lastname: Zhou
authors.forename: Wei-Min
authors.initials: WM
authors.lastname: Lim
authors.forename: Tobias C
authors.initials: TC
authors.lastname: Cornvik
authors.forename: Christiane
authors.initials: C
authors.lastname: Ruedl
authors.forename: Susana G
authors.initials: SG
authors.lastname: Shochat
authors.forename: Suet-Mien
authors.initials: SM
authors.lastname: Tan
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D016764:Cell Polarity; D019204:GTP-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D055767:Immobilized Proteins / Q000737:chemistry / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000737:chemistry / Q000378:metabolism; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism
chemical_list: C477322:FERMT3 protein, human; D055767:Immobilized Proteins; D016169:Lymphocyte Function-Associated Antigen-1; D008565:Membrane Proteins; D009363:Neoplasm Proteins; C419368:RACK1 protein, human; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface; D018799:Intercellular Adhesion Molecule-1; D019204:GTP-Binding Proteins