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

Kobayashi, Minatsu; Iwamatsu, Akihiro; Shinohara-Kanda, Azusa; Ihara, Sayoko; Fukui, Yoshihiro

doi:10.1038/sj.onc.1206256

Cited by 42 publications

(36 citation statements)

References 37 publications

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“…2B). Other studies have shown that LY294002 down-regulates MUC1 in gastric carcinoma cells (36). By contrast, LY294002 had no apparent effect on MUC1 expression in 3Y1/MUC1 cells, indicating that MUC1 is regulated by PI3K-independent pathways (Fig.…”

Section: Muc1mentioning

confidence: 72%

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The MUC1 Oncoprotein Activates the Anti-apoptotic Phosphoinositide 3-Kinase/Akt and Bcl-xL Pathways in Rat 3Y1 Fibroblasts

Raina

Kharbanda

Küfe

2004

Journal of Biological Chemistry

154

144

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The MUC1 transmembrane glycoprotein is overexpressed by most human carcinomas. Overexpression of MUC1 confers transformation; however, the signaling pathways activated by this oncoprotein are largely unknown. The present studies demonstrated that MUC1-induced transformation of 3Y1 fibroblasts is associated with increased levels of phospho-Akt and phospho-Bad. The finding that LY294002 blocks MUC1-mediated increases in phospho-Akt and phospho-Bad supports the involvement of phosphoinositide 3-kinase (PI3K) as an upstream effector of this response. We also show that MUC1 increases the expression of the anti-apoptotic Bcl-x L protein (but not Bcl-2) by a PI3K-independent mechanism. In concert with these results, MUC1 attenuated (i) the loss of mitochondrial transmembrane potential, (ii) mitochondrial cytochrome c release, (iii) activation of caspase-9, and (iv) induction of apoptosis by the antimetabolite, 1-␤-D-arabinofuranosylcytosine. Similar results were obtained with the anti-cancer agent, gemcitabine. These findings indicate that expression of MUC1 in 3Y1 cells activates the anti-apoptotic PI3K/Akt and Bcl-x L pathways.The phosphoinositide 3-kinase (PI3K) 1 /Akt signaling pathway is of importance in promoting cell survival. PI3K, which consists of a p85 regulatory subunit and a p110 catalytic subunit, phosphorylates phosphatidylinositols (PIs) at their 3-position and thereby converts PI(4,5)P 2 to PI(3,4,5)P 3 (1). The serine-threonine Akt/PKB kinase and the phosphoinositide-dependent kinase 1 (PDK1) localize at cell membrane sites by direct binding to PI(3,4,5)P 3 through their pleckstrin-homology domains (2, 3). Phosphorylation of Akt by PDK1 stimulates Akt activity (4). In turn, Akt phosphorylates and inactivates the Forkhead-related transcription factor 1 by retaining it in the cytosol in a complex with 14-3-3 proteins. Similarly, Akt phosphorylates Bad, induces binding of Bad to 14-3-3 proteins, and prevents Bad from interacting with the anti-apoptotic Bcl-2 and Bcl-x L proteins (5). The activity of the pro-death caspase-9 protease is inhibited by Akt-mediated phosphorylation (6). Akt can also confer cell survival by indirect regulation of NF-B through I B kinase (7, 8) and of p53 through Mdm2 (9, 10). These findings, and the demonstration that PI3K/Akt signaling is dysregulated in human malignancies, have provided support for the significance of this pathway in conferring tumor cell survival (11).The human DF3/MUC1 transmembrane glycoprotein is expressed on the apical borders of normal secretory epithelial cells (12). The MUC1 protein is synthesized as a single polypeptide that is cleaved in the endoplasmic reticulum into N-terminal and C-terminal subunits, which then reside as heterodimers at the apical cell surface (13,14). The large (Ͼ250 kDa) N-terminal ectodomain (N-ter) contains variable numbers of 20-amino acid tandem repeats that are heavily glycosylated (15, 16). The smaller (ϳ25 kDa) C-terminal subunit (C-ter) consists of an extracellular domain of 58 amino acids, a 28-amino acid transmembrane...

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Section: Muc1mentioning

confidence: 72%

“…Activates the PI3K/Akt Pathway-PI3K is aberrantly activated in diverse human carcinomas (1,11,36). Interaction of the PI3K p85 subunit with phosphotyrosine residues of activated growth factor receptors or adaptor proteins results in stimulation of the PI3K p110 catalytic subunit.…”

Section: Muc1mentioning

confidence: 99%

The MUC1 Oncoprotein Activates the Anti-apoptotic Phosphoinositide 3-Kinase/Akt and Bcl-xL Pathways in Rat 3Y1 Fibroblasts

Raina

Kharbanda

Küfe

2004

Journal of Biological Chemistry

154

144

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“…343 Strong evidence for a key role for ERBB3 in gastric malignancy came from a study of poorly differentiated signet-ring cell gastric carcinomas. 344 Activation of ERBB3 and complexation with PI3K were associated with the de-differentiated state; expression of a chimera of activated ERBB2/ERBB3 resulted in increased malignancy of an initially highly differentiated cell line.…”

Section: Melanomasmentioning

confidence: 99%

The ERBB3 receptor in cancer and cancer gene therapy

2008

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ERBB3, a member of the epidermal growth factor receptor (EGFR) family, is unique in that its tyrosine kinase domain is functionally defective. It is activated by neuregulins, by other ERBB and nonERBB receptors as well as by other kinases, and by novel mechanisms. Downstream it interacts prominently with the phosphoinositol 3-kinase/AKT survival/mitogenic pathway, but also with GRB, SHC, SRC, ABL, rasGAP, SYK and the transcription regulator EBP1. There are likely important but poorly understood roles for nuclear localization and for secreted isoforms. Studies of ERBB3 expression in primary cancers and of its mechanistic contributions in cultured cells have implicated it, with varying degrees of certainty, with causation or sustenance of cancers of the breast, ovary, prostate, certain brain cells, retina, melanocytes, colon, pancreas, stomach, oral cavity and lung. Recent results link high ERBB3 activity with escape from therapy targeting other ERBBs in lung and breast cancers. Thus a wide and centrally important role for ERBB3 in cancer is becoming increasingly apparent. Several approaches for targeting ERBB3 in cancers have been tested or proposed. Small inhibitory RNA (siRNA) to ERBB3 or AKT is showing promise as a therapeutic approach to treatment of lung adenocarcinoma.

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“…Recently, we found that PI 3-kinase was often activated by binding to ErbB3 in signet-ring cell lines (Kobayashi et al, 2003). In these cells, ErbB2 was activated as well, suggesting that the ErbB2/ErbB3 complex may play a role in the formation of signet-ring cell carcinomas.…”

Section: Introductionmentioning

confidence: 99%

“…In these cells, ErbB2 was activated as well, suggesting that the ErbB2/ErbB3 complex may play a role in the formation of signet-ring cell carcinomas. Introduction of constitutively active ErbB3 in a differentiated adenocarcinoma cell line, HCC2998, resulted in loss of cell-cell contact and high expression of mucin (MUC1), a marker of malignant tumors (Yonezawa and Sato, 1997;Kobayashi et al, 2003). However, the function of the downstream molecules of PI 3-kinase in the formation of signet-ring cell carcinoma remains elusive.…”

Section: Introductionmentioning

confidence: 99%

The PI 3-kinase-Rac-p38 MAP kinase pathway is involved in the formation of signet-ring cell carcinoma

Karouji

Kobayashi

et al. 2003

Oncogene

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Signet-ring cell carcinoma is classified in poorly differentiated adenocarcinoma with an aggressive nature and a poor prognosis. We have shown that the activation of PI 3-kinase in highly differentiated adenocarcinomas induces loss of cell-cell contact and formation of vacuoles, giving phenotypes similar to those of signet-ring cell lines. SB203580, a potent p38 MAP kinase inhibitor, blocked this transition, and expression of an active form of MKK6 (MKK6DA), an activator of p38 MAP kinase, gave effects similar to those induced by expression of the active form of PI 3-kinase (BD110), although formation of large vacuoles was not induced. Activation of MKK3, another activator of p38 MAP kinase, was activated in native signet-ring carcinoma cell lines. Anchorage-independent growth of signet-ring cell lines was inhibited by LY294002 or SB203580. These results suggest that p38 MAP kinase is functioning downstream of PI 3-kinase in signaling of the malignant phenotype. Secretion of mucins was enhanced in BD110-expressing cells, but not in MKK6DA-expressing cells, suggesting that secretion of mucins is independent of the MKK6-p38 MAP kinase cascade. Thus, there may be at least two pathways, p38 MAP kinase-dependent and -independent, which are involved in regulation of cell-cell contact and the protein secretion system, respectively.

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

Cited by 42 publications

References 37 publications

The MUC1 Oncoprotein Activates the Anti-apoptotic Phosphoinositide 3-Kinase/Akt and Bcl-xL Pathways in Rat 3Y1 Fibroblasts

The MUC1 Oncoprotein Activates the Anti-apoptotic Phosphoinositide 3-Kinase/Akt and Bcl-xL Pathways in Rat 3Y1 Fibroblasts

The ERBB3 receptor in cancer and cancer gene therapy

The PI 3-kinase-Rac-p38 MAP kinase pathway is involved in the formation of signet-ring cell carcinoma

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