title: SHARPIN is an endogenous inhibitor of β1-integrin activation.
abstract: Regulated activation of integrins is critical for cell adhesion, motility and tissue homeostasis. Talin and kindlins activate β1-integrins, but the counteracting inhibiting mechanisms are poorly defined. We identified SHARPIN as an important inactivator of β1-integrins in an RNAi screen. SHARPIN inhibited β1-integrin functions in human cancer cells and primary leukocytes. Fibroblasts, leukocytes and keratinocytes from SHARPIN-deficient mice exhibited increased β1-integrin activity, which was fully rescued by re-expression of SHARPIN. We found that SHARPIN directly binds to a conserved cytoplasmic region of integrin α-subunits and inhibits recruitment of talin and kindlin to the integrin. Therefore, SHARPIN inhibits the critical switching of β1-integrins from inactive to active conformations.
authors.affiliation: Medical Biotechnology, VTT Technical Research Centre of Finland, 20521 Turku, Finland.
authors.forename: Juha K
authors.initials: JK
authors.lastname: Rantala
authors.forename: Jeroen
authors.initials: J
authors.lastname: Pouwels
authors.forename: Teijo
authors.initials: T
authors.lastname: Pellinen
authors.forename: Stefan
authors.initials: S
authors.lastname: Veltel
authors.forename: Petra
authors.initials: P
authors.lastname: Laasola
authors.forename: Elina
authors.initials: E
authors.lastname: Mattila
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Potter
authors.forename: Ted
authors.initials: T
authors.lastname: Duffy
authors.forename: John P
authors.initials: JP
authors.lastname: Sundberg
authors.forename: Olli
authors.initials: O
authors.lastname: Kallioniemi
authors.forename: Janet A
authors.initials: JA
authors.lastname: Askari
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Humphries
authors.forename: Maddy
authors.initials: M
authors.lastname: Parsons
authors.forename: Marko
authors.initials: M
authors.lastname: Salmi
authors.forename: Johanna
authors.initials: J
authors.lastname: Ivaska
mesh_terms: D000818:Animals; D001665:Binding Sites; D045744:Cell Line, Tumor; D002465:Cell Movement; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D019012:Integrin beta1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015603:Keratinocytes / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D025941:Protein Interaction Mapping; D021122:Protein Subunits; D034622:RNA Interference; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship; D016608:Talin / Q000378:metabolism; D014162:Transfection
chemical_list: D019012:Integrin beta1; D008024:Ligands; D009419:Nerve Tissue Proteins; D021122:Protein Subunits; D011993:Recombinant Fusion Proteins; D016608:Talin; C425287:sharpin