Volume 272, Number 35, Issue of August 29, 1997 pp. 22207-22214
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

Functional Mapping of the Cytoplasmic Region of Intercellular Adhesion Molecule-3 Reveals Important Roles for Serine Residues

(Received for publication, May 5, 1997, and in revised form, July 1, 1997)

From ICOS Corporation, Bothell, Washington 98021

Intercellular adhesion molecule-3 (ICAM-3), a ligand for ₂ integrins, elicits a variety of activation responses in lymphocytes. We describe a functional mapping study that focuses on the 37-residue cytoplasmic region of ICAM-3. Carboxyl-terminal truncations delineated portions involved in T cell antigen receptor costimulation, homotypic aggregation, and cellular spreading. Truncation of the membrane distal 25 residues resulted in loss of T cell antigen receptor costimulation as determined by interleukin 2 secretion. Aggregation and cell spreading were sensitive to truncation of the membrane distal and proximal thirds of the cytoplasmic portion. Phosphoamino acid analysis revealed that ICAM-3 from activated cells contained phosphoserine and phosphopeptide mapping identified Ser⁴⁸⁹ as a site of phosphorylation in vivo. Mutation of Ser⁴⁸⁹ or Ser⁵¹⁵ to alanine blocked interleukin 2 secretion, aggregation and cell spreading, while mutation of other serine residues affected only a subset of functions. Ser⁴⁸⁹ was a phosphorylation site in vitro for recombinant protein kinase C. Finally, treatment of Jurkat cells with chelerythrine chloride, a protein kinase C inhibitor, prevented ICAM-3-triggered spreading. This study delineates separable regions and amino acid residues within the cytoplasmic portion of ICAM-3 that are important for T cell function.

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