title: Macrophages require Skap2 and Sirpα for integrin-stimulated cytoskeletal rearrangement.
abstract: Macrophages migrate to sites of insult during normal inflammatory responses. Integrins guide such migration, but the transmission of signals from integrins into the requisite cytoskeletal changes is poorly understood. We have discovered that the hematopoietic adaptor protein Skap2 is necessary for macrophage migration, chemotaxis, global actin reorganization and local actin reorganization upon integrin engagement. Binding of phosphatidylinositol [3,4,5]-triphosphate to the Skap2 pleckstrin-homology (PH) domain, which relieves its conformational auto-inhibition, is critical for this integrin-driven cytoskeletal response. Skap2 enables integrin-induced tyrosyl phosphorylation of Src-family kinases (SFKs), Adap, and Sirpα, establishing their roles as signaling partners in this process. Furthermore, macrophages lacking functional Sirpα unexpectedly have impaired local integrin-induced responses identical to those of Skap2(-/-) macrophages, and Skap2 requires Sirpα for its recruitment to engaged integrins and for coordinating downstream actin rearrangement. By revealing the positive-regulatory role of Sirpα in a Skap2-mediated mechanism connecting integrin engagement with cytoskeletal rearrangement, these data demonstrate that Sirpα is not exclusively immunoinhibitory, and illuminate previously unexplained observations implicating Skap2 and Sirpα in mouse models of inflammatory disease.
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115,  USA.
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Alenghat
authors.forename: Quentin J
authors.initials: QJ
authors.lastname: Baca
authors.forename: Nooreen T
authors.initials: NT
authors.lastname: Rubin
authors.forename: Lily I
authors.initials: LI
authors.lastname: Pao
authors.forename: Takashi
authors.initials: T
authors.lastname: Matozaki
authors.forename: Clifford A
authors.initials: CA
authors.lastname: Lowell
authors.forename: David E
authors.initials: DE
authors.lastname: Golan
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Neel
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Swanson
mesh_terms: D008841:Actin Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002417:Cattle; D002633:Chemotaxis / Q000187:drug effects; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D016023:Integrins / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000378:metabolism*; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D058105:Polymerization / Q000187:drug effects; D017434:Protein Structure, Tertiary; D011971:Receptors, Immunologic / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D016023:Integrins; D047908:Intracellular Signaling Peptides and Proteins; C501922:Sirpa protein, mouse; D011971:Receptors, Immunologic; C116431:src kinase associated phosphoprotein 2; D016173:Macrophage Colony-Stimulating Factor