The carboxyl-terminal region of biliary glycoprotein controls its tyrosinephosphorylation and association with protein-tyrosine phosphatases SHP-1 and SHP-2 in epithelial cells

Biliary glycoprotein (Bgp, C-CAM, or CD66a) is an immunoglobulin-like cell adhesion molecule and functions as a tumor suppressor protein. We have prev iously shown that the Bgp1 isoform responsible for inhibition of colonic, l iver, prostate, and breast tumor cell growth contains within its cytoplasmi c domain two tyrosine residues positioned in immunoreceptor tyrosine-based inhibition motif (ITIM) consensus sequences. Moreover, we determined that t hese residues, upon phosphorylation, associate with the protein-tyrosine ph osphatase SHP-1. In this report, we have further evaluated the structural b ases of the association of Bgp1 with Tyr phosphatases. First, we demonstrat e that Bgp1 also associates with the SHP-2 Tyr phosphatase, but not with an unrelated Tyr phosphatase, PTP-PEST, Association of Bgp1 and SHP-2 involve s the Tyr residues within the Bgp1 ITIM sequences, Val at position +3 relat ive to the second Tyr (Tyr-515), and the SHP-2 N-terminal SH2 domain. In ad dition, our results indicate that residues +4, +5, and +6 relative to Tyr-5 15 in the Bgp1 cytoplasmic domain play a significant role in these interact ions, as their deletion reduced Bgp1 Tyr phosphorylation and association wi th SHP-1 and SHP-2 by as much as 80%. Together, these results indicate that both SHP-1 and SHP-2 interact with the Bgp1 cytoplasmic domain via ITIM-li ke sequences. Furthermore, they reveal that the C-terminal amino acids of B gp1 are critical for these interactions.