title: Actin cytoskeleton reorganization by Syk regulates Fcγ receptor responsiveness by increasing its lateral mobility and clustering.
abstract: Clustering of immunoreceptors upon association with multivalent ligands triggers important responses including phagocytosis, secretion of cytokines, and production of immunoglobulins. We applied single-molecule detection and tracking methods to study the factors that control the mobility and clustering of phagocytic Fcγ receptors (FcγR). While the receptors exist as monomers in resting macrophages, two distinct populations were discernible based on their mobility: some diffuse by apparent free motion, while others are confined within submicron boundaries that reduce the frequency of spontaneous collisions. Src-family and Syk kinases determine the structure of the actin cytoskeleton, which is fenestrated, accounting for the heterogeneous diffusion of the FcγR. Stimulation of these kinases during phagocytosis induces reorganization of the cytoskeleton both locally and distally in a manner that alters receptor mobility and clustering, generating a feedback loop that facilitates engagement of FcγR at the tip of pseudopods, directing the progression of phagocytosis.
authors.affiliation: Program in Cell Biology, Hospital for Sick Children, Toronto, ON M5G1X8, Canada.
authors.forename: Valentin
authors.initials: V
authors.lastname: Jaumouillé
authors.affiliation: Program in Cell Biology, Hospital for Sick Children, Toronto, ON M5G1X8, Canada.
authors.forename: Yoav
authors.initials: Y
authors.lastname: Farkash
authors.affiliation: Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390-8816, USA.
authors.forename: Khuloud
authors.initials: K
authors.lastname: Jaqaman
authors.affiliation: Department of Integrative Biology, University of Colorado Denver, Denver, CO 80204, USA.
authors.forename: Raibatak
authors.initials: R
authors.lastname: Das
authors.affiliation: Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143-0100, USA.
authors.forename: Clifford A
authors.initials: CA
authors.lastname: Lowell
authors.affiliation: Program in Cell Biology, Hospital for Sick Children, Toronto, ON M5G1X8, Canada; Keenan Research Centre of the Li Ka Shing Knowledge Institute, St. Michael's Hospital, 209 Victoria Street, Toronto, ON M5C 1N8, Canada. Electronic address: sergio.grinstein@sickkids.ca.
authors.forename: Sergio
authors.initials: S
authors.lastname: Grinstein
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism*; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D021962:Membrane Microdomains / Q000378:metabolism; D010587:Phagocytosis / Q000502:physiology*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D017452:Receptors, IgG / Q000378:metabolism*; D015398:Signal Transduction; D000072377:Syk Kinase; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: C445323:FCGR2A protein, human; D047908:Intracellular Signaling Peptides and Proteins; D017452:Receptors, IgG; D002784:Cholesterol; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; D019061:src-Family Kinases