Regulation of β1-integrin-mediated cell adhesion by the Cbl adaptor protein

Traci Zell, Christopher S. Warden, Anissa S.H. Chan, Molly E. Cook, Cheryl L. Dell, Stephen W. Hunt, Yoji Shimizu

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Background: Leukocyte activation results in a rapid increase in adhesion to the extracellular matrix due to the activation of β1 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 β1 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.

Original languageEnglish (US)
Pages (from-to)814-822
Number of pages9
JournalCurrent Biology
Issue number14
StatePublished - Jul 2 1998

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    Zell, T., Warden, C. S., Chan, A. S. H., Cook, M. E., Dell, C. L., Hunt, S. W., & Shimizu, Y. (1998). Regulation of β1-integrin-mediated cell adhesion by the Cbl adaptor protein. Current Biology, 8(14), 814-822.