The Carboxyl-terminal Region of Biliary Glycoprotein Controls Its Tyrosine Phosphorylation and Association with Protein-tyrosine Phosphatases SHP-1 and SHP-2 in Epithelial Cells

Abstract

Biliary glycoprotein (Bgp, C-CAM, or CD66a) is an immunoglobulin-like cell adhesion molecule and functions as a tumor suppressor protein. We have previously shown that the Bgp1 isoform responsible for inhibition of colonic, liver, prostate, and breast tumor cell growth contains within its cytoplasmic domain two tyrosine residues positioned in immunoreceptor tyrosine-based inhibition motif (ITIM) consensus sequences. Moreover, we determined that these residues, upon phosphorylation, associate with the protein-tyrosine phosphatase SHP-1. In this report, we have further evaluated the structural bases of the association of Bgp1 with Tyr phosphatases. First, we demonstrate 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 involves the Tyr residues within the Bgp1 ITIM sequences, Val at position ؉3 relative to the second Tyr (Tyr-515), and the SHP-2 N-terminal SH2 domain. In addition, our results indicate that residues ؉4, ؉5, and ؉6 relative to Tyr-515 in the Bgp1 cytoplasmic domain play a significant role in these interactions, as their deletion reduced Bgp1 Tyr phosphorylation and association with 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-like sequences. Furthermore, they reveal that the C-terminal amino acids of Bgp1 are critical for these interactions.

CEACAM1 (CD66a) mediates delay of spontaneous and Fas ligand-induced apoptosis in granulocytes

“…SHP-1 is known to bind to the cytoplasmic domain of CEACAM1-L upon tyrosine phosphorylation, thereby being activated [26]. Thus, our finding that CEACAM1 ligation in the granulocytes increased both CEACAM1 tyrosine phosphorylation and CEACAM1/SHP-1 association, suggests that SHP-1 activation is an upstream event in the Erk1/2 activation, leading to CEACAM1-induced delay of apoptosis.…”

CEACAM1 Dynamics during Neisseria gonorrhoeae Suppression of CD4+ T Lymphocyte Activation

“…Previous studies concerning the role of CEACAM1 in epithelial cell cancers (47) and in an immortalized B cell line (31) have indicated that the SHP-1 and SHP-2 phosphatases can both associate with CEACAM1. Neisserial binding to CEACAM1 has been reported to suppress SHP-1 activity in monocytes (39).…”

The CEACAM1-mediated apoptosis pathway is activated by CEA and triggers dual cleavage of CEACAM1

“…The cytoplasmic domains of CEACAM1 are phosphorylated at their serine residues (Edlund et al, 1998;Fournes et al, 2001) and bind to calmodulin (Edlund et al, 1996). The CEACAM1-4L domain contains two tyrosine residues that recruit and activate pp60 c-src (Brummer et al, 1995) or the phosphatases SHP1 and -2 (Huber et al, 1999) upon phosphorylation. Signal transduction through the cytoplasmic domains appears to be important for the tumour suppressor function of CEACAM1 that has been initially suggested by clinical studies (Neumaier et al, 1993b;Nollau et al, 1997b) and subsequently by in vitro experiments and animal studies (Kunath et al, 1995;Obrink, 1997;Singer et al, 2000).…”