Activation of ErbB3-PI3-kinase pathway is correlated with malignant phenotypes of adenocarcinomas

• Published in: Oncogene Vol. 22; no. 9; pp. 1294 - 1301
• Main Authors: KOBAYASHI, Michimoto, IWAMATSU, Akihiro, SHINOHARA-KANDA, Azusa, IHARA, Sayoko, FUKUI, Yasuhisa
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 06.03.2003; Nature Publishing Group
• Subjects: 1-Phosphatidylinositol 3-kinase; Adenocarcinoma; Adenocarcinoma - enzymology; Adenocarcinoma - pathology; Amino Acid Motifs; Amino Acid Sequence; Antigens, Neoplasm - biosynthesis; Antigens, Neoplasm - genetics; Biological and medical sciences; Cancer; Carcinoma; Carcinoma, Signet Ring Cell - enzymology; Carcinoma, Signet Ring Cell - pathology; Cell Differentiation; Cell physiology; Cell Polarity; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Colonic Neoplasms - enzymology; Colonic Neoplasms - pathology; Enzyme Activation; ErbB-2 protein; ErbB-3 protein; Fundamental and applied biological sciences. Psychology; Gastric cancer; Gene Expression Regulation, Neoplastic; Genes, erbB; Genes, erbB-2; Humans; Molecular and cellular biology; Molecular Sequence Data; Mucin-1 - biosynthesis; Mucin-1 - genetics; Neoplasm Proteins - isolation & purification; Neoplasm Proteins - physiology; Phenotype; Phenotypes; Phosphatidylinositol 3-Kinases - physiology; Phosphorylation; Protein Processing, Post-Translational; Receptor, ErbB-2 - genetics; Receptor, ErbB-2 - physiology; Receptor, ErbB-3 - isolation & purification; Receptor, ErbB-3 - physiology; Recombinant Fusion Proteins - physiology; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Stomach Neoplasms - enzymology; Stomach Neoplasms - pathology; Tumor cell lines; Tumors; Tyrosine; Adenocarcinoma; Human; signet-ring cell carcinoma; Phosphorylation; Purification; gastric cancer; Enzyme; Transferases; ErbB3; Cell cell interaction; Molecular interaction; Identification; Gene expression; Signal transduction; Cell line; Protein kinase; Dedifferentiation; mucin; Gastric disease; phosphatidylinositol 3-kinase
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1206256

Signet-ring cell carcinomas are malignant dedifferentiated carcinomas, which are frequently found in the stomach. We previously demonstrated that a 200 kDa protein is often constitutively phosphorylated on tyrosine and bound to phosphatidylinositol 3-kinase (PI3-kinase) in signet-ring cell carcinoma cells. In this study, we purified the 200 kDa protein from an extract of NUGC-4 cells, a cell line of signet-ring cell carcinoma, and identified it as ErbB3. ErbB3 was found to be phosphorylated selectively in dedifferentiated adenocarcinoma cell lines among various gastric cancer cell lines. Expression of a constitutively active chimeric receptor consisting of ErbB2 and ErbB3 in HCC2998 cells, a highly differentiated adenocarcinoma cell line, revealed that the signaling triggered by phosphorylation of ErbB3 was important for dedifferentiated phenotypes such as loss of cell-cell interaction and high expression of MUC1/DF3 antigen, a marker of the malignant tumors. Taken together, activation of ErbB3 pathway may contribute to the development of dedifferentiated carcinomas.