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

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

doi:10.1038/sj.onc.1204058

Cited by 40 publications

(35 citation statements)

References 45 publications

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“…The shorter form (CEACAM1-S) of CEACAM1 includes a cytoplasmic tail of only 10 residues. Structural and functional analyses have suggested that the adhesive activity of CEACAM1 is mediated by the first extracellular immunoglobulin domain while the cytoplasmic domain is necessary and sufficient for growth regulatory functions (Fournes et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

“…CEACAM1 also participates in signal transduction via the cytoplasmic domain that undergoes phosphorylation (Izzi et al, 1999;Estrera et al, 2001;Fournes et al, 2001) impacting cell proliferation and differentiation. CEACAM1 phosphorylation has been reported in colon and prostate cancers at tyrosine (Tyr-488) and serine (Ser-503) residues (Izzi et al, 1999;Estrera et al, 2001;Fournes et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

“…CEACAM1 phosphorylation has been reported in colon and prostate cancers at tyrosine (Tyr-488) and serine (Ser-503) residues (Izzi et al, 1999;Estrera et al, 2001;Fournes et al, 2001). Point mutation of Tyr-488 was sufficient to reverse the in vivo tumor growth inhibition while substitution or deletion of Ser-503 leads to reversal of tumor inhibition (Izzi et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

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CEACAM1 impedes thyroid cancer growth but promotes invasiveness: a putative mechanism for early metastases

Winer

et al. 2006

Oncogene

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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CEACAM1 impedes thyroid cancer growth but promotes invasiveness: a putative mechanism for early metastases

Winer

et al. 2006

Oncogene

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“…It is composed of four extracellular domains and a long (CEACAM1-4L) or short (CEACAM1-4S) cytoplasmic domain which are encoded by alternative splicing (Hinoda et al, 1988;Barnett et al, 1989). 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.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2008

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Marked reduction in apoptosis is a hallmark of early colon tumour growth and the vast majority of these tumours exhibit a loss of expression of the glycoprotein carcinoembryonic-antigen-related cell adhesion molecule 1 (CEACAM1). We recently reported that the CEACAM1 functions as a mediator of apoptosis implicating this cell surface protein in early tumour development. However, the mechanistic involvement of CEACAM1 in cell death pathways is unclear. Here, we show that apoptosis triggers cleavage of the long form of CEACAM1 (CEACAM1-4L) at intracellular and extracellular sites in Jurkat cells and HEK293 cells. Signalling through CEACAM1 leads to caspase activation including caspase-1 and -3 and also involves non-caspase proteases. Moreover, we provide evidence that the naturally occurring CEACAM family member CEA is an inducer of CEACAM1-mediated apoptosis in HT29 colon cancer cells, an effect that depends on the abundance of CEACAM1 on the cell surface. Together, our results demonstrate that the CEACAM1-dependent cell death pathway involves dual cleavage of CEACAM1 and caspase activation and can be activated by CEA.

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“…Importantly, CEACAM1 is also a substrate of the insulin receptor (IR). IR-mediated phosphorylation of CEACAM1 14 results in binding and sequestration of the Shc adaptor protein, 15,16 thus potentially limiting insulin signaling. Additionally, CEACAM1 modulates hepatic insulin clearance.…”

mentioning

confidence: 99%

Vitamin D inhibits CEACAM1 to promote insulin/IGF-I receptor signaling without compromising anti-proliferative action

Liu

Guo

Ezzat

et al. 2011

Laboratory Investigation

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Population studies suggest putative links between vitamin D (VD)-deficiency and risk of cancer and diabetes. The insulin/ IGF-I receptor represents a signaling target of the carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) that is implicated in both diabetes and cancer, therefore we hypothesized that VD actions may be mediated through this adhesion molecule. In this study, we show that 1,25 vitamin D3 and its analogues EB1089 and KH1060 potently inhibit CEACAM1 expression in cancer cells. This effect was associated with significant reductions in mRNA and protein levels, resulting from transcriptional and posttranslational actions respectively. Insulin/IGF-I-mediated IRS-1 and Akt activation were enhanced by VD treatment. Similarly, CEACAM1 downregulation significantly upregulated the insulin and IGF-I receptors and mimicked the effect of VD-mediated enhanced insulin/IGF-I receptor signaling. Despite improved insulin/ IGF-I signaling, the anti-proliferative actions of VD were preserved in the absence or presence of forced CEACAM1 expression. Forced CEACAM1, however, abrogated the anti-invasive actions of VD. Our findings highlight CEACAM1 as a target of VD action. The resulting inhibition of CEACAM1 has potentially beneficial effects on metabolic disorders without necessarily compromising the anticancer properties of this vitamin.

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

Cited by 40 publications

References 45 publications

CEACAM1 impedes thyroid cancer growth but promotes invasiveness: a putative mechanism for early metastases

CEACAM1 impedes thyroid cancer growth but promotes invasiveness: a putative mechanism for early metastases

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

Vitamin D inhibits CEACAM1 to promote insulin/IGF-I receptor signaling without compromising anti-proliferative action

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