Activation of ErbB3-PI3-kinase pathway is correlated with malignant phenotypes of adenocarcinomas.
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.
Kobayashi
Michimoto
M
Laboratory of Biological Chemistry, Department of Applied Biological Chemistry, Faculty of Agricultural and Life Science, University of Tokyo, Japan.
Iwamatsu
Akihiro
A
Shinohara-Kanda
Azusa
A
Ihara
Sayoko
S
Fukui
Yasuhisa
Y
D000230:Adenocarcinoma / Q000201:enzymology* / Q000473:pathology; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D018279:Carcinoma, Signet Ring Cell / Q000201:enzymology* / Q000473:pathology; D002454:Cell Differentiation; D016764:Cell Polarity; D003110:Colonic Neoplasms / Q000201:enzymology / Q000473:pathology; D004789:Enzyme Activation; D015972:Gene Expression Regulation, Neoplastic; D018815:Genes, erbB; D018734:Genes, erbB-2; D006801:Humans; D008969:Molecular Sequence Data; D018396:Mucin-1 / Q000096:biosynthesis / Q000235:genetics; D009363:Neoplasm Proteins / Q000302:isolation & purification / Q000502:physiology*; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000502:physiology; D020893:Receptor, ErbB-3 / Q000302:isolation & purification / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013274:Stomach Neoplasms / Q000201:enzymology* / Q000473:pathology
D000951:Antigens, Neoplasm; D018396:Mucin-1; D009363:Neoplasm Proteins; D019869:Phosphatidylinositol 3-Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D011993:Recombinant Fusion Proteins