title: HS1 functions as an essential actin-regulatory adaptor protein at the immune synapse.
abstract: HS1, the leukocyte-specific homolog of cortactin, regulates F-actin in vitro and is phosphorylated in response to TCR ligation, but its role in lymphocyte activation has not been addressed. We demonstrate that HS1-deficient T cells fail to accumulate F-actin at the immune synapse (IS) and, upon TCR ligation, form actin-rich structures that are disordered and unstable. Early TCR activation events are intact in these cells, but Ca2+ influx and IL-2 gene transcription are defective. Importantly, HS1 tyrosine phosphorylation is required for its targeting to the IS and for its function in regulating actin dynamics and IL-2 promoter activity. Phosphorylation also links HS1 to multiple signaling proteins, including Lck, PLCgamma1, and Vav1, and is essential for the stable recruitment of Vav1 to the IS. Taken together, our studies show that HS1 is indispensable for signaling events leading to actin assembly and IL-2 production during T cell activation.
authors.affiliation: Department of Immunology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905.
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Gomez
authors.affiliation: Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Sean D
authors.initials: SD
authors.lastname: McCarney
authors.affiliation: Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Esteban
authors.initials: E
authors.lastname: Carrizosa
authors.affiliation: Department of Pathology, University of Chicago, Chicago, Illinois 60637.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Labno
authors.affiliation: Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Erin O
authors.initials: EO
authors.lastname: Comiskey
authors.affiliation: Department of Immunology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Nolz
authors.affiliation: Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania 19104.
authors.forename: Peimin
authors.initials: P
authors.lastname: Zhu
authors.affiliation: Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania 19104.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Freedman
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois 60637.
authors.forename: Marcus R
authors.initials: MR
authors.lastname: Clark
authors.affiliation: Department of Pediatrics, Department of Immunology, University of Washington School of Medicine, Seattle, Washington 98195.
authors.forename: David J
authors.initials: DJ
authors.lastname: Rawlings
authors.affiliation: Department of Immunology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905; Division of Oncology Research, Mayo Clinic College of Medicine, Rochester, Minnesota 55905. Electronic address: billadeau.daniel@mayo.edu.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Billadeau
authors.affiliation: Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania 19104. Electronic address: jburkhar@mail.med.upenn.edu.
authors.forename: Janis K
authors.initials: JK
authors.lastname: Burkhardt
mesh_terms: D000199:Actins / Q000032:analysis / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001798:Blood Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics*; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D051966:Phospholipase C gamma / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D051567:Proto-Oncogene Proteins c-vav / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000819:agonists / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D014158:Transcription, Genetic; D014443:Tyrosine / Q000378:metabolism
chemical_list: D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D001798:Blood Proteins; C061909:HCLS1 protein, human; D007376:Interleukin-2; D051567:Proto-Oncogene Proteins c-vav; D011948:Receptors, Antigen, T-Cell; C496619:Vav1 protein, mouse; D014443:Tyrosine; D051966:Phospholipase C gamma; D002118:Calcium