DOI: 10.1083/jcb.143.5.1375. Tumor Suppressor PTEN Inhibits Integrin- and Growth Factor–mediated Mitogen-activated Protein (MAP) Kinase Signaling Pathways

Tumor Suppressor PTEN Inhibits Integrin- and Growth Factor–mediated Mitogen-activated Protein (MAP) Kinase Signaling Pathways

10.1083/jcb.143.5.1375

Crossref journal-article

Rockefeller University Press

The Journal of Cell Biology (291)

Abstract

The tumor suppressor PTEN dephosphorylates focal adhesion kinase (FAK) and inhibits integrin-mediated cell spreading and cell migration. We demonstrate here that expression of PTEN selectively inhibits activation of the extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) pathway. PTEN expression in glioblastoma cells lacking the protein resulted in inhibition of integrin-mediated MAP kinase activation. Epidermal growth factor (EGF) and platelet-derived growth factor (PDGF)- induced MAPK activation were also blocked. To determine the specific point of inhibition in the Ras/Raf/ MEK/ERK pathway, we examined these components after stimulation by fibronectin or growth factors. Shc phosphorylation and Ras activity were inhibited by expression of PTEN, whereas EGF receptor autophosphorylation was unaffected. The ability of cells to spread at normal rates was partially rescued by coexpression of constitutively activated MEK1, a downstream component of the pathway. In addition, focal contact formation was enhanced as indicated by paxillin staining. The phosphatase domain of PTEN was essential for all of these functions, because PTEN with an inactive phosphatase domain did not suppress MAP kinase or Ras activity. In contrast to its effects on ERK, PTEN expression did not affect c-Jun NH2-terminal kinase (JNK) or PDGF-stimulated Akt. Our data suggest that a general function of PTEN is to down-regulate FAK and Shc phosphorylation, Ras activity, downstream MAP kinase activation, and associated focal contact formation and cell spreading.

Bibliography

Gu, J., Tamura, M., & Yamada, K. M. (1998). Tumor Suppressor PTEN Inhibits Integrin- and Growth Factorâmediated Mitogen-activated Protein (MAP) Kinase Signaling Pathways. The Journal of Cell Biology, 143(5), 1375â1383.

Authors 3

Jianguo Gu (first)
Masahito Tamura (additional)
Kenneth M. Yamada (additional)

References 46 Referenced 264

10.1016/0092-8674(91)90636-D / Cell / Molecular themes in oncogenesis by Bishop (1991)
10.1016/S0021-9258(18)47058-5 / J Biol Chem / Integrin-mediated cell adhesion activates mitogen-activated protein kinases by Chen (1994)
10.1074/jbc.271.30.18122 / J Biol Chem / Integrin-mediated activation of MEK and mitogen-activated protein kinase is independent of Ras by Chen (1996)
{'key': '2023072900162525500_B4', 'first-page': '2331', 'article-title': 'Suppression of tumorigenicity of glioblastoma cells by adenovirus-mediated MMAC1/PTEN gene transfer', 'volume': '58', 'author': 'Cheney', 'year': '1998', 'journal-title': 'Cancer Res'} / Cancer Res / Suppression of tumorigenicity of glioblastoma cells by adenovirus-mediated MMAC1/PTEN gene transfer by Cheney (1998)
10.1074/jbc.271.25.14814 / J Biol Chem / Ras activation is necessary for integrin-mediated activation of extracellular signal-regulated kinase 2 and cytosolic phospholipase A2 but not for cytoskeletal organization by Clark (1996)
10.1016/0092-8674(94)90133-3 / Cell / Activation of MAP kinase kinase is necessary and sufficient for PC12 differentiation and for transformation of NIH 3T3 cells by Cowley (1994)
10.1172/JCI117350 / J Clin Invest / Extracellular matrix modulates epidermal growth factor receptor activation in rat glomerular epithelial cells by Cybulsky (1994)
10.1016/0092-8674(94)90380-8 / Cell / JNK1: a protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain by Derijard (1994)
10.1073/pnas.94.23.12479 / Proc Natl Acad Sci USA / Growth suppression of glioma cells by PTEN requires a functional phosphatase catalytic domain by Furnari (1997)
10.1016/S0092-8674(00)81892-9 / Cell / Suppression of integrin activation: a novel function of a Ras/Raf-initiated MAP kinase pathway by Hughes (1997)
10.1016/0092-8674(92)90115-S / Cell / Integrins: versatility, modulation, and signaling in cell adhesion by Hynes (1992)
10.1128/MCB.16.3.1027 / Mol Cell Biol / Ras-induced activation of Raf-1 is dependent on tyrosine phosphorylation by Jelinek (1996)
10.1128/MCB.17.8.4406 / Mol Cell Biol / Phosphatidylinositol 3-kinase is required for integrin-stimulated AKT and Raf-1/mitogen-activated protein kinase pathway activation by King (1997)
10.1038/ng1097-143 / Nat Genet / PTEN1 is frequently mutated in primary endometrial carcinomas by Kong (1997)
10.1016/0378-1119(89)90220-5 / Gene / Molecular analysis of the pac gene encoding a puromycin N-acetyl transferase from Streptomyces alboniger by Lacalle (1989)
10.1083/jcb.126.5.1287 / J Cell Biol / Single subunit chimeric integrins as mimics and inhibitors of endogenous integrin functions in receptor localization, cell spreading and migration, and matrix assembly by LaFlamme (1994)
10.1126/science.275.5308.1943 / Science / PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer by Li (1997)
10.1038/ng0597-64 / Nat Genet / Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome by Liaw (1997)
10.1083/jcb.136.6.1385 / J Cell Biol / Integrin-mediated activation of MAP kinase is independent of FAK: evidence for dual integrin signaling pathways in fibroblasts by Lin (1997)
10.1074/jbc.273.22.13375 / J Biol Chem / The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate by Maehama (1998)
10.1126/science.8052857 / Science / Transformation of mammalian cells by constitutively active MAP kinase kinase by Mansour (1994)
10.1038/ng0897-333 / Nat Genet / Germline mutations in PTEN are present in Bannayan-Zonana syndrome by Marsh (1997)
10.1093/emboj/16.4.706 / EMBO (Eur Mol Biol Organ) J / Opposite effects of the p52shc/p46shc and p66shc splicing isoforms on the EGF receptor-MAP kinase-fos signaling pathway by Migliaccio (1997)
10.1083/jcb.135.6.1633 / J Cell Biol / Integrins can collaborate with growth factors for phosphorylation of receptor tyrosine kinases and MAP kinase activation: roles of integrin aggregation and occupancy of receptors by Miyamoto (1996)
10.1074/jbc.270.1.269 / J Biol Chem / Matrix/integrin interaction activates the mitogen-activated protein kinase, p44erk-1 and p42erk-2 by Morino (1995)
10.1073/pnas.94.17.9052 / Proc Natl Acad Sci USA / P-TEN, the tumor suppressor from human chromosome 10q23, is a dual-specificity phosphatase by Myers (1997)
10.1093/hmg/6.8.1383 / Hum Mol Genet / Germline mutations in the PTEN/MMAC1 gene in patients with Cowden disease by Nelen (1997)
{'key': '2023072900162525500_B28', 'first-page': '1149', 'article-title': 'MAP kinase activation is essential for oncogenic transformation of NIH3T3 cells by Mos', 'volume': '10', 'author': 'Okazaki', 'year': '1995', 'journal-title': 'Oncogene'} / Oncogene / MAP kinase activation is essential for oncogenic transformation of NIH3T3 cells by Mos by Okazaki (1995)
10.1073/pnas.90.18.8319 / Proc Natl Acad Sci USA / Mitogen-activated protein kinases p42mapk and p44mapk are required for fibroblast proliferation by Pages (1993)
10.1038/373573a0 / Nature / protein modules and signaling networks by Pawson (1995)
{'key': '2023072900162525500_B31', 'first-page': '1575', 'article-title': 'Involvement of Shc in insulin- and epidermal growth factor-induced activation of p21ras', 'volume': '14', 'author': 'Pronk', 'year': '1994', 'journal-title': 'Mol Cell Biol'} / Mol Cell Biol / Involvement of Shc in insulin- and epidermal growth factor-induced activation of p21ras by Pronk (1994)
10.1093/emboj/16.18.5592 / EMBO (Eur Mol Biol Organ) J / Growth factor activation of MAP kinase requires cell adhesion by Renshaw (1997)
10.1002/bies.950170309 / Bioessays / Signal transduction through integrins: a central role for focal adhesion kinase? by Richardson (1995)
10.1038/360689a0 / Nature / Association of the Shc and Grb2/Sem5 SH2-containing proteins is implicated in activation of the Ras pathway by tyrosine kinase by Rozakis-Adcock (1992)
10.1016/S0955-0674(97)80112-3 / Curr Opin Cell Biol / Cell-to-cell contact and extracellular matrix by Ruoslahti (1997)
10.1074/jbc.272.20.13189 / J Biol Chem / Focal adhesion kinase overexpression enhances ras-dependent integrin signaling to ERK2/mitogen-activated protein kinase through interactions with and activation of c-Src by Schlaepfer (1997)
10.1038/372786a0 / Nature / Integrin-mediated signal transduction linked to Ras pathway by GRB2 binding to focal adhesion kinase by Schlaepfer (1994)
10.1128/MCB.18.5.2571 / Mol Cell Biol / Multiple Grb2-mediated integrin-stimulated signaling pathways to ERK2/mitogen-activated protein kinase: summation of both c-Src- and focal adhesion kinase-initiated tyrosine phosphorylation events by Schlaepfer (1998)
10.1083/jcb.139.3.575 / J Cell Biol / Integrins, oncogenes, and anchorage independence by Schwartz (1997)
10.1146/annurev.cb.11.110195.003001 / Annu Rev Cell Dev Biol / Integrins: emerging paradigms of signal transduction by Schwartz (1995)
10.1038/ng0497-356 / Nat Genet / Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers by Steck (1997)
10.1126/science.280.5369.1614 / Science / Inhibition of cell migration, spreading, and focal adhesions by tumor suppressor PTEN by Tamura (1998)
10.1016/S0092-8674(00)81392-6 / Cell / The adaptor protein Shc couples a class of integrins to the control of cell cycle progression by Wary (1996)
10.1016/S0092-8674(00)81604-9 / Cell / A requirement for caveolin-1 and associated kinase fyn in integrin signaling and anchorage-dependent cell growth by Wary (1998)
10.1128/MCB.17.4.1947 / Mol Cell Biol / Megakaryocytic differentiation induced by constitutive activation of mitogen-activated protein kinase kinase by Whalen (1997)
10.1016/0955-0674(95)80110-3 / Curr Opin Cell Biol / Integrin transmembrane signaling and cytoskeletal control by Yamada (1995)

Dates

Type	When
Created	23 years, 1 month ago (July 26, 2002, 12:45 p.m.)
Deposited	2 years ago (July 28, 2023, 8:17 p.m.)
Indexed	1 month, 3 weeks ago (July 2, 2025, 2:45 p.m.)
Issued	26 years, 8 months ago (Nov. 30, 1998)
Published	26 years, 8 months ago (Nov. 30, 1998)
Published Online	26 years, 8 months ago (Nov. 30, 1998)
Published Print	26 years, 8 months ago (Nov. 30, 1998)

Funders 0

None

BibTeX

@article{Gu_1998, title={Tumor Suppressor PTEN Inhibits Integrin- and Growth Factor–mediated Mitogen-activated Protein (MAP) Kinase Signaling Pathways}, volume={143}, ISSN={1540-8140}, url={http://dx.doi.org/10.1083/jcb.143.5.1375}, DOI={10.1083/jcb.143.5.1375}, number={5}, journal={The Journal of Cell Biology}, publisher={Rockefeller University Press}, author={Gu, Jianguo and Tamura, Masahito and Yamada, Kenneth M.}, year={1998}, month=nov, pages={1375–1383} }

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      "author": "Chen",
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      "volume": "271",
      "author": "Chen",
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      "article-title": "Ras activation is necessary for integrin-mediated activation of extracellular signal-regulated kinase 2 and cytosolic phospholipase A2 but not for cytoskeletal organization",
      "volume": "271",
      "author": "Clark",
      "year": "1996",
      "journal-title": "J Biol Chem"
    },
    {
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      "first-page": "841",
      "DOI": "10.1016/0092-8674(94)90133-3",
      "article-title": "Activation of MAP kinase kinase is necessary and sufficient for PC12 differentiation and for transformation of NIH 3T3 cells",
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      "author": "Cowley",
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      "journal-title": "Cell"
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      "first-page": "68",
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      "article-title": "Extracellular matrix modulates epidermal growth factor receptor activation in rat glomerular epithelial cells",
      "volume": "94",
      "author": "Cybulsky",
      "year": "1994",
      "journal-title": "J Clin Invest"
    },
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      "doi-asserted-by": "crossref",
      "first-page": "1025",
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      "author": "Miyamoto",
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      "first-page": "9052",
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      "volume": "94",
      "author": "Myers",
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      "journal-title": "Proc Natl Acad Sci USA"
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