Faculty Collaboration Database

Inhibition of antigen-receptor signaling by Platelet Endothelial Cell Adhesion Molecule-1 (CD31) requires functional ITIMs, SHP-2, and p56(lck). Blood 2001 Apr 15;97(8):2351-7

Date

04/06/2001

Pubmed ID

11290597

DOI

10.1182/blood.v97.8.2351

Scopus ID

2-s2.0-0035871812 (requires institutional sign-in at Scopus site)   116 Citations

Abstract

Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1, CD31) is a 130-kd member of the immunoglobulin gene superfamily that is expressed on the surface of platelets, endothelial cells, myeloid cells, and certain lymphocyte subsets. PECAM-1 has recently been shown to contain functional immunoreceptor tyrosine-based inhibitory motifs (ITIMs) within its cytoplasmic domain, and co-ligation of PECAM-1 with the T-cell antigen receptor (TCR) results in tyrosine phosphorylation of PECAM-1, recruitment of Src homology 2 domain-containing protein tyrosine phosphatase-2 (SHP-2), and attenuation of TCR-mediated cellular signaling. To determine the molecular basis of PECAM-1 inhibitory signaling in lymphocytes, the study sought to (1) establish the importance of the PECAM-1 ITIMs for its inhibitory activity, (2) determine the relative importance of SHP-2 versus SHP-1 in mediating the inhibitory effect of PECAM-1, and (3) identify the protein tyrosine kinases required for PECAM-1 tyrosine phosphorylation in T cells. Co-ligation of wild-type PECAM-1 with the B-cell antigen receptor expressed on chicken DT40 B cells resulted in a marked reduction of calcium mobilization-similar to previous observations in T cells. In contrast, co-ligation of an ITIM-less form of PECAM-1 had no inhibitory effect. Furthermore, wild-type PECAM-1 was unable to attenuate calcium mobilization in SHP-2-deficient DT40 variants despite abundant levels of SHP-1 in these cells. Finally, PECAM-1 failed to become tyrosine phosphorylated in p56(lck)-deficient Jurkat T cells. Together, these data provide important insights into the molecular requirements for PECAM-1 regulation of antigen receptor signaling.

Author List

Newman DK, Hamilton C, Newman PJ

Authors

Debra K. Newman PhD Investigator in the Blood Research Institute department at BloodCenter of Wisconsin
Debra K. Newman PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Amino Acid Motifs
Animals
Antibodies, Monoclonal
CD3 Complex
Calcium Signaling
Chickens
Humans
Intracellular Signaling Peptides and Proteins
Jurkat Cells
Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
Phosphorylation
Platelet Endothelial Cell Adhesion Molecule-1
Protein Phosphatase 2
Protein Processing, Post-Translational
Protein Tyrosine Phosphatase, Non-Receptor Type 11
Protein Tyrosine Phosphatase, Non-Receptor Type 6
Protein Tyrosine Phosphatases
Receptors, Antigen, T-Cell
Recombinant Fusion Proteins
SH2 Domain-Containing Protein Tyrosine Phosphatases
Structure-Activity Relationship
Transfection
src Homology Domains