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The CEACAM1-L Ser503 residue is crucial for inhibition of colon cancer cell tumorigenicity

Oncogene volume 20, pages 219–230 (2001)Cite this article

Abstract

CEACAM1 (also known as biliary glycoprotein, C-CAM or CD66a) is a cell adhesion molecule of the immunoglobulin family behaving as a tumor inhibitory protein in colon, prostate, liver, endometrial and breast cancers. Inhibition of tumor development is dependent upon the presence of the long 71–73 amino acid cytoplasmic domain of the CEACAM1 protein (CEACAM1-L). We have recently defined a number of cis-acting motifs within the long cytoplasmic domain participating in tumor cell growth inhibition. These are Tyr488, corresponding to an Immunoreceptor Tyrosine-based Inhibition Motif, as well as the three terminal lysine residues of the protein. In this study, we provide evidence that treatment with phorbol esters leads to increased phosphorylation of in vivo 32P-labeled CEACAM1-L in mouse CT51 carcinoma cells, in the mouse 1MEA 7R.1 liver carcinoma cells and in 293 human embryonic kidney cells transfected with the Ceacam1-L cDNA. Basal level Ser phosphorylation was abrogated by treatment with the staurosporine inhibitor, but not by the protein kinase C-specific inhibitor calphostin C or other inhibitors such as H7 or sphingosine. Specific inhibitors of protein kinase A or calmodulin kinase had only minimal effects on the levels of basal or PMA-induced Ser phosphorylation. Furthermore, PMA treatment of the CT51 cells induced cell spreading and cellular relocalization of the CEACAM1-L protein. Since Ser503 has been described as a PMA-induced phosphorylation site in other cell systems, we investigated whether Ser503 was involved in these responses in mouse intestinal cells. No differences were noticed in the basal or the PMA-induced phosphorylation levels, kinase inhibitor sensitivity or the PMA-induced relocalization of the protein between the wild-type and the Ser503Ala mutant CEACAM1-L. However, we provide evidence that Ser503 participates in CEACAM1-L-mediated tumor inhibition as its mutation to an Ala led to in vivo tumor development, contrary to the tumor inhibitory phenotype observed with the wild-type CEACAM1-L protein.

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Abbreviations

N-CAM:

neural cell adhesion molecule

CEA:

carcinoembryonic antigen

Bgp or BGP:

biliary glycoprotein

CEACAM1:

carcinoembryonic antigen cell adhesion molecule 1

TPA or PMA:

phorbol 12-myristate 13-acetate

PKC:

protein kinase C

MDCK:

Mardin-Darby canine kidney cells

VEGF:

vascular endothelial growth factor

PCR:

polymerase chain reaction

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Acknowledgements

We are greatly indebted to Philippe Grondin for preliminary experiments, to Anne-Claude Gingras (McGill University) and Dr André Veillette (Institut de Recherches Cliniques de Montréal) for advice during the course of this work and critical reading of the manuscript. We also thank Dr Kathryn V Holmes (Department of Microbiology, University of Colorado) for the CC1 antibody. This research was supported by the Cancer Research Society Inc. B Fournès is funded by the ‘Association pour la Recherche sur le Cancer’, N Beauchemin is supported by a ‘Chercheur National’ program from the ‘Fonds de la Recherche en Santé du Québec’.

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  1. Bénédicte Fournès and Svetlana Sadekova: B Fournès and S Sadekova contributed equally to the work

Authors and Affiliations

  1. McGill Cancer Centre, McGill University, Montreal, H3G 1Y6, Québec, Canada

    Bénédicte Fournès, Svetlana Sadekova, Claire Turbide, Stéphanie Létourneau & Nicole Beauchemin

  2. Department of Biochemistry, McGill University, Montreal, H3G 1Y6, Québec, Canada

    Nicole Beauchemin

  3. Department of Medicine, McGill University, Montreal, H3G 1Y6, Québec, Canada

    Nicole Beauchemin

  4. Department of Oncology, McGill University, Montreal, H3G 1Y6, Québec, Canada

    Nicole Beauchemin

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Fournès, B., Sadekova, S., Turbide, C. et al. The CEACAM1-L Ser503 residue is crucial for inhibition of colon cancer cell tumorigenicity. Oncogene 20, 219–230 (2001). https://doi.org/10.1038/sj.onc.1204058

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