CEACAM1 long isoform has opposite effects on the growth of human mastocytosis and medullary thyroid carcinoma cells

Abstract

Carcinoembryonic antigen‐related cell adhesion molecule 1 (CEACAM1) is expressed in a number of tumor cell types. The immunoreceptor tyrosine‐based inhibitory motif (ITIM)‐containing isoforms of this molecule which possess a long cytoplasmic tail (CEACAM1‐L) generally play inhibitory roles in cell function by interacting with Src homology 2 domain‐containing tyrosine phosphatase (SHP)‐1 and/or SHP‐2. Src family kinases (SFKs) are also known to bind to and phosphorylate CEACAM1‐L isoforms. Here, we report that CEACAM1 was uniquely expressed at high levels in both human neoplastic mast cells (mastocytosis) and medullary thyroid carcinoma cell (MTC) lines, when compared with their expression in nonneoplastic mast cells or nonneoplastic C cells. This expression was mainly derived from CEACAM1‐L isoforms based upon assessment of CEACAM1 mRNA expression. CEACAM1 knockdown upregulated cell growth of HMC1.2 cells harboring KIT mutations detected in clinical mastocytosis, whereas downregulated the growth of TT cells harboring RET mutations detected in clinical MTCs. Immunoblotting, ELISA and immunoprecipitaion analysis showed that activated SHP‐1 is preferentially associated with CEACAM1 in HMC1.2 cells harboring KIT mutations, whereas Src family kinases (SFKs) are preferentially associated with CEACAM1 in TT cells harboring RET mutations. These studies suggest that the dominantly interacting proteins SHP1 or SFK determine whether CEACAM1‐L displays a positive or negative role in tumor cells.

Killer Immunoglobulin-Like Receptor 2DL4 (CD158d) Regulates Human Mast Cells both Positively and Negatively: Possible Roles in Pregnancy and Cancer Metastasis

“…Studies using mast cell-deficient mice, such as Kit W/Wv mice and Kit Wsh/Wsh mice, revealed that mast cells protect against parasitic infections including Strongyloides ratti and Strongyloides brasiliensis [7,8], as well as the venoms of honeybees or vipers [9]. Mast cells are (KIR) 2DL4 [19][20][21][22][23][24][25][26][27][28][29][30][31]. These include inhibitory receptors characterized by immunoreceptor tyrosine-based inhibitory motifs (ITIMs) within their cytosolic domains ( Figure 1) [32].…”

NKp46 regulates the production of serine proteases and IL‐22 in human mast cells in urticaria pigmentosa

“…Several receptors have been reported to suppress mastocytosis growth . The effects are commonly mediated by phosphatases including Src homology domain 2‐containing protein tyrosine phosphatases (SHPs) and SH2 homology domain‐containing inositol 5′‐phosphatases (SHIPs).…”

Up‐regulation of microRNA‐30b/30d cluster represses hepatocyte apoptosis in mice with fulminant hepatic failure by inhibiting CEACAM1

“…It has been suggested by Zhang et al that miR‐30d was degraded in human colon cancer cell lines in contrast to normal colon epithelial cell line . As for dysregulation of CEACAM1, a recent study has unveiled that CEACAM1 exerted a high expression in multiple myeloma, and Ueshima et al have provided evidence that expression of CEACAM1 was heightened in both neoplastic mast cells and medullary thyroid carcinoma cell lines …”