Regulation of β1-integrin-mediated cell adhesion by the CbI adaptor protein
| Autor: | Traci Zell, Christopher S. Warden, Molly E. Cook, Cheryl L. Dell, Anissa S.H. Chan, Yoji Shimizu, Stephen W. Hunt |
|---|---|
| Jazyk: | angličtina |
| Předmět: |
Recombinant Fusion Proteins
Ubiquitin-Protein Ligases Green Fluorescent Proteins Integrin CD2 Antigens HL-60 Cells chemical and pharmacologic phenomena Biology Polymerase Chain Reaction CD49c General Biochemistry Genetics and Molecular Biology Collagen receptor Phosphatidylinositol 3-Kinases chemistry.chemical_compound CD28 Antigens Antigens CD Proto-Oncogene Proteins Cell Adhesion Humans Proto-Oncogene Proteins c-cbl Phosphotyrosine Cell adhesion Binding Sites Agricultural and Biological Sciences(all) Biochemistry Genetics and Molecular Biology(all) Integrin beta1 Tyrosine phosphorylation hemic and immune systems Flow Cytometry Molecular biology Cell biology Kinetics Luminescent Proteins Amino Acid Substitution Integrin alpha M chemistry Mutagenesis Site-Directed biology.protein Tetradecanoylphorbol Acetate Integrin beta 6 General Agricultural and Biological Sciences Proto-oncogene tyrosine-protein kinase Src |
| Zdroj: | Current Biology. (14):814-822 |
| ISSN: | 0960-9822 |
| DOI: | 10.1016/S0960-9822(98)70323-9 |
| Popis: | Background: Leukocyte activation results in a rapid increase in adhesion to the extracellular matrix due to the activation of β 1 integrin receptors. A role for phosphatidylinositol (PI) 3-kinase in integrin activation has been proposed, as activation of integrins by many receptors can be blocked by PI 3-kinase inhibitors. One receptor that regulates integrins is the CD28 surface antigen; here, we investigated the mechanisms responsible for CD28-mediated integrin activation. Results: CD28-mediated integrin activation was blocked by mutation of the binding site for the p85 catalytic subunit of PI 3-kinase in the CD28 cytoplasmic domain, and by expression of a dominant-negative form of the p85 subunit. Substitution of the Src homology 2 (SH2)-binding motif in the CD28 cytoplasmic domain for the corresponding motif in the CD28-related CTLA-4 surface antigen also blocked integrin activation but did not affect the recruitment and activation of PI 3-kinase. Mutations of the CD28 cytoplasmic domain that blocked integrin activation also impaired the tyrosine phosphorylation of the Cbl adaptor protein and the activation of the PI 3-kinase that was associated with Cbl. This Cbl-associated PI 3-kinase was distinct from the PI 3-kinase that coprecipitated with the CD28 cytoplasmic domain. CD28-mediated activation of β 1 integrins was inhibited by expression of a mutant Cbl protein that shows reduced association with PI 3-kinase. Conclusions: Cbl is required for PI-3-kinase-dependent regulation of integrin receptors by CD28. Furthermore, CD28 is coupled to two distinct pools of PI 3-kinase, one directly associated with the CD28 cytoplasmic tail and the other associated with Cbl. |
| Databáze: | OpenAIRE |
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