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Molecular and Cellular Biology, September 1998, p. 5291-5307, Vol. 18, No. 9
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Identification of a Proline-Rich Sequence in the CD2 Cytoplasmic Domain Critical for Regulation of Integrin-Mediated Adhesion and Activation of Phosphoinositide 3-Kinase

Wendy J. Kivens,1 Stephen W. Hunt III,2 James L. Mobley,1,dagger Traci Zell,1 Cheryl L. Dell,2 Barbara E. Bierer,3 and Yoji Shimizu1,*

Department of Laboratory Medicine and Pathology, Center for Immunology, and Cancer Center, University of Minnesota Medical School, Minneapolis, Minnesota 554551; Department of Immunopathology, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 481052; and The Dana Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 021153

Received 8 April 1998/Accepted 10 June 1998

The CD2 molecule is one of several lymphocyte receptors that rapidly initiates signaling events regulating integrin-mediated cell adhesion. CD2 stimulation of resting human T cells results within minutes in an increase in beta 1-integrin-mediated adhesion to fibronectin. We have utilized the HL60 cell line to map critical residues within the CD2 cytoplasmic domain involved in CD2 regulation of integrin function. A panel of CD2 cytoplasmic domain mutants was constructed and analyzed for their ability to upregulate integrin-mediated adhesion to fibronectin. Mutations in the CD2 cytoplasmic domain implicated in CD2-mediated interleukin-2 production or CD2 avidity do not affect CD2 regulation of integrin activity. A proline-rich sequence, K-G-P-P-L-P (amino acids 299 to 305), is essential for CD2-mediated regulation of beta 1 integrin activity. CD2-induced increases in beta 1 integrin activity could be blocked by two phosphoinositide 3-kinase (PI 3-K) inhibitors or by overexpression of a dominant negative form of the p85 subunit of PI 3-K. In addition, CD2 cytoplasmic domain mutations that abrogate CD2-induced increases in integrin-mediated adhesion also ablate CD2-induced increases in PI 3-K enzymatic activity. Surprisingly, CD2 cytoplasmic domain mutations that inhibit CD2 regulation of adhesion do not affect the constitutive association of the p85 subunit of PI 3-K association with CD2. Mutation of the proline residues in the K-G-P-P-L-P motif to alanines prevented CD2-mediated activation of integrin function and PI 3-K activity but not mitogen-activated protein (MAP) kinase activity. Furthermore, the MEK inhibitor PD 098059 blocked CD2-mediated activation of MAP kinase but had no effect on CD2-induced adhesion. These studies identify a proline-rich sequence in CD2 critical for PI 3-K-dependent regulation of beta 1 integrin adhesion by CD2. In addition, these studies suggest that CD2-mediated activation of MAP kinase is not involved in CD2 regulation of integrin adhesion.

* Corresponding author. Mailing address: Department of Laboratory Medicine and Pathology, Center for Immunology, University of Minnesota Medical School, Box 609 UMHC, 420 Delaware Street S.E., Minneapolis, MN 55455-0385. Phone: (612) 626-6849. Fax: (612) 625-2199. E-mail: shimi002{at}tc.umn.edu.

dagger Present address: Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, MI 48105.

Molecular and Cellular Biology, September 1998, p. 5291-5307, Vol. 18, No. 9
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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