CEACAM1 long isoform has opposite effects on the growth of human mastocytosis and medullary thyroid carcinoma cells.
CEACAM1 long isoform has opposite effects on the growth of human mastocytosis and medullary thyroid carcinoma cells.
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DOI：
10.1002/cam4.1050
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发表时间：
2017-04
期刊：
影响因子：
4
通讯作者：
Haga H
中科院分区：
文献类型：
--
作者：
Ueshima C;Kataoka TR;Takei Y;Hirata M;Sugimoto A;Hirokawa M;Okayama Y;Blumberg RS;Haga H
癌胚抗原相关细胞粘附分子1（CEACAM 1）在许多肿瘤细胞类型中表达。该分子的含有免疫受体酪氨酸抑制基序（ITIM）的同种型具有长胞质尾（CEACAM 1-L），通常通过与含有Src同源2结构域的酪氨酸磷酸酶（SHP）-1和/或SHP-2相互作用在细胞功能中发挥抑制作用。Src家族激酶（SFK）也已知结合并磷酸化CEACAM 1-L同种型。在这里，我们报告，CEACAM 1是唯一的表达在人类肿瘤肥大细胞（肥大细胞增多症）和甲状腺髓样癌细胞（MTC）线高水平时，与他们的表达在非肿瘤肥大细胞或非肿瘤C细胞。基于CEACAM 1 mRNA表达的评估，该表达主要来源于CEACAM 1-L亚型。CEACAM 1敲低上调了在临床肥大细胞增多症中检测到的携带KIT突变的HMC 1.2细胞的细胞生长，而下调了在临床MTC中检测到的携带RET突变的TT细胞的生长。免疫印迹、ELISA和免疫沉淀分析显示，在携带KIT突变的HMC 1.2细胞中，活化的SHP-1优先与CEACAM 1相关，而在携带RET突变的TT细胞中，Src家族激酶（SFK）优先与CEACAM 1相关。这些研究表明，主要相互作用蛋白SHP 1或SFK决定了CEACAM 1-L在肿瘤细胞中是发挥积极作用还是消极作用。
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.