J. Cell Biol., Volume 143, Number 5, November 30, 1998 1375-1383

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

Jianguo Gu, Masahito Tamura, and Kenneth M. Yamada

Craniofacial Developmental Biology and Regeneration Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892-4370

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.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

• Oudit, G. Y., Kassiri, Z., Zhou, J., Liu, Q. C., Liu, P. P., Backx, P. H., Dawood, F., Crackower, M. A., Scholey, J. W., Penninger, J. M. (2008). Loss of PTEN attenuates the development of pathological hypertrophy and heart failure in response to biomechanical stress. Cardiovasc Res 78: 505-514 [Abstract] [Full Text]  
• Li, Y., Guessous, F., Kwon, S., Kumar, M., Ibidapo, O., Fuller, L., Johnson, E., Lal, B., Hussaini, I., Bao, Y., Laterra, J., Schiff, D., Abounader, R. (2008). PTEN Has Tumor-Promoting Properties in the Setting of Gain-of-Function p53 Mutations. Cancer Res. 68: 1723-1731 [Abstract] [Full Text]  
• Dey, N., Crosswell, H. E., De, P., Parsons, R., Peng, Q., Su, J. D., Durden, D. L. (2008). The Protein Phosphatase Activity of PTEN Regulates Src Family Kinases and Controls Glioma Migration. Cancer Res. 68: 1862-1871 [Abstract] [Full Text]  
• Tamguney, T., Stokoe, D. (2007). New insights into PTEN. J. Cell Sci. 120: 4071-4079 [Abstract] [Full Text]  
• Sun, Y., St. Clair, D. K., Fang, F., Warren, G. W., Rangnekar, V. M., Crooks, P. A., St. Clair, W. H. (2007). The radiosensitization effect of parthenolide in prostate cancer cells is mediated by nuclear factor-{kappa}B inhibition and enhanced by the presence of PTEN. Molecular Cancer Therapeutics 6: 2477-2486 [Abstract] [Full Text]  
• Guo, H.-B., Randolph, M., Pierce, M. (2007). Inhibition of a Specific N-Glycosylation Activity Results in Attenuation of Breast Carcinoma Cell Invasiveness-related Phenotypes: INHIBITION OF EPIDERMAL GROWTH FACTOR-INDUCED DEPHOSPHORYLATION OF FOCAL ADHESION KINASE. J. Biol. Chem. 282: 22150-22162 [Abstract] [Full Text]  
• Blanco-Aparicio, C., Renner, O., Leal, J. F.M., Carnero, A. (2007). PTEN, more than the AKT pathway. Carcinogenesis 28: 1379-1386 [Abstract] [Full Text]  
• Pezzolesi, M. G., Zbuk, K. M., Waite, K. A., Eng, C. (2007). Comparative genomic and functional analyses reveal a novel cis-acting PTEN regulatory element as a highly conserved functional E-box motif deleted in Cowden syndrome. Hum Mol Genet 16: 1058-1071 [Abstract] [Full Text]  
• Chang, F., Lemmon, C. A., Park, D., Romer, L. H. (2007). FAK Potentiates Rac1 Activation and Localization to Matrix Adhesion Sites: A Role for betaPIX. Mol. Biol. Cell 18: 253-264 [Abstract] [Full Text]  
• Suphapeetiporn, K., Kongkam, P., Tantivatana, J., Sinthuwiwat, T., Tongkobpetch, S., Shotelersuk, V. (2006). PTEN c.511C>T Nonsense Mutation in a BRRS Family Disrupts a Potential Exonic Splicing Enhancer and Causes Exon Skipping. Jpn J Clin Oncol 36: 814-821 [Abstract] [Full Text]  
• Rafiq, K., Kolpakov, M. A., Abdelfettah, M., Streblow, D. N., Hassid, A., Dell'Italia, L. J., Sabri, A. (2006). Role of Protein-tyrosine Phosphatase SHP2 in Focal Adhesion Kinase Down-regulation during Neutrophil Cathepsin G-induced Cardiomyocytes Anoikis. J. Biol. Chem. 281: 19781-19792 [Abstract] [Full Text]  
• Lee, S. Y., Kang, E. J., Hur, G. Y., Jung, K. H., Jung, H. C., Lee, S. Y., Kim, J. H., Shin, C., In, K. H., Kang, K. H., Yoo, S. H., Shim, J. J. (2006). Peroxisome proliferator-activated receptor-{gamma} inhibits cigarette smoke solution-induced mucin production in human airway epithelial (NCI-H292) cells. Am. J. Physiol. Lung Cell. Mol. Physiol. 291: L84-L90 [Abstract] [Full Text]  
• Yao, D., Alexander, C. L., Quinn, J. A., Porter, M. J., Wu, H., Greenhalgh, D. A. (2006). PTEN Loss Promotes rasHa-Mediated Papillomatogenesis via Dual Up-Regulation of AKT Activity and Cell Cycle Deregulation but Malignant Conversion Proceeds via PTEN-Associated Pathways. Cancer Res. 66: 1302-1312 [Abstract] [Full Text]  
• Stoker, A. W (2005). Protein tyrosine phosphatases and signalling. J Endocrinol 185: 19-33 [Abstract] [Full Text]  
• Grizzle, W. E., Bostwick, D. G., Burke, H., Tawfik, O. W., McGregor, D., Cohn, J., Lieberman, R. (2005). Biomarkers in Prostate Cancer. aacredbook 2005: 196-204 [Full Text]  
• Khyrul, W. A. K. M., LaLonde, D. P., Brown, M. C., Levinson, H., Turner, C. E. (2004). The Integrin-linked Kinase Regulates Cell Morphology and Motility in a Rho-associated Kinase-dependent Manner. J. Biol. Chem. 279: 54131-54139 [Abstract] [Full Text]  
• Eason, R. R., Velarde, M. C., Chatman, L. Jr, Till, S. R., Geng, Y., Ferguson, M., Badger, T. M., Simmen, R. C. M. (2004). Dietary Exposure to Whey Proteins Alters Rat Mammary Gland Proliferation, Apoptosis, and Gene Expression during Postnatal Development. J. Nutr. 134: 3370-3377 [Abstract] [Full Text]  
• Sinha, D., Bannergee, S., Schwartz, J. H., Lieberthal, W., Levine, J. S. (2004). Inhibition of Ligand-independent ERK1/2 Activity in Kidney Proximal Tubular Cells Deprived of Soluble Survival Factors Up-regulates Akt and Prevents Apoptosis. J. Biol. Chem. 279: 10962-10972 [Abstract] [Full Text]  
• Musatov, S., Roberts, J., Brooks, A. I., Pena, J., Betchen, S., Pfaff, D. W., Kaplitt, M. G. (2004). Inhibition of neuronal phenotype by PTEN in PC12 cells. Proc. Natl. Acad. Sci. USA 101: 3627-3631 [Abstract] [Full Text]  
• Goberdhan, D. C.I., Wilson, C. (2003). PTEN: tumour suppressor, multifunctional growth regulator and more. Hum Mol Genet 12: R239-248 [Abstract] [Full Text]  
• Wu, W., Wang, X., Zhang, W., Reed, W., Samet, J. M., Whang, Y. E., Ghio, A. J. (2003). Zinc-induced PTEN Protein Degradation through the Proteasome Pathway in Human Airway Epithelial Cells. J. Biol. Chem. 278: 28258-28263 [Abstract] [Full Text]  
• Govindarajan, B., Bai, X., Cohen, C., Zhong, H., Kilroy, S., Louis, G., Moses, M., Arbiser, J. L (2003). Malignant Transformation of Melanocytes to Melanoma by Constitutive Activation of Mitogen-activated Protein Kinase Kinase (MAPKK) Signaling. J. Biol. Chem. 278: 9790-9795 [Abstract] [Full Text]  
• Vijayan, K. V., Liu, Y., Dong, J.-F., Bray, P. F. (2003). Enhanced Activation of Mitogen-activated Protein Kinase and Myosin Light Chain Kinase by the Pro33 Polymorphism of Integrin beta 3. J. Biol. Chem. 278: 3860-3867 [Abstract] [Full Text]  
• Gupta, R., Ting, J. T. L., Sokolov, L. N., Johnson, S. A., Luan, S. (2002). A Tumor Suppressor Homolog, AtPTEN1, Is Essential for Pollen Development in Arabidopsis. Plant Cell 14: 2495-2507 [Abstract] [Full Text]  
• Weng, L.-P., Brown, J. L., Baker, K. M., Ostrowski, M. C., Eng, C. (2002). PTEN blocks insulin-mediated ETS-2 phosphorylation through MAP kinase, independently of the phosphoinositide 3-kinase pathway. Hum Mol Genet 11: 1687-1696 [Abstract] [Full Text]  
• Knobbe, C. B., Merlo, A., Reifenberger, G. (2002). Pten signaling in gliomas. Neuro Oncol 4: 196-211 [Abstract]  
• Fox, J. A., Ung, K., Tanlimco, S. G., Jirik, F. R. (2002). Disruption of a Single Pten Allele Augments the Chemotactic Response of B Lymphocytes to Stromal Cell-Derived Factor-1. J. Immunol. 169: 49-54 [Abstract] [Full Text]  
• You, L., Ebner, S., Kruse, F. E. (2001). Glial Cell-Derived Neurotrophic Factor (GDNF)-Induced Migration and Signal Transduction in Corneal Epithelial Cells. IOVS 42: 2496-2504 [Abstract] [Full Text]  
• Weng, L.-P., Smith, W. M., Brown, J. L., Eng, C. (2001). PTEN inhibits insulin-stimulated MEK/MAPK activation and cell growth by blocking IRS-1 phosphorylation and IRS-1/Grb-2/Sos complex formation in a breast cancer model. Hum Mol Genet 10: 605-616 [Abstract] [Full Text]  
• Rescan, C., Coutant, A., Talarmin, H., Theret, N., Glaise, D., Guguen-Guillouzo, C., Baffet, G. (2001). Mechanism in the Sequential Control of Cell Morphology and S Phase Entry by Epidermal Growth Factor Involves Distinct MEK/ERK Activations. Mol. Biol. Cell 12: 725-738 [Abstract] [Full Text]  
• Prasad, N., Topping, R. S., Decker, S. J. (2001). SH2-Containing Inositol 5'-Phosphatase SHIP2 Associates with the p130Cas Adapter Protein and Regulates Cellular Adhesion and Spreading. Mol. Cell. Biol. 21: 1416-1428 [Abstract] [Full Text]  
• Yamada, K. M., Araki, M. (2001). Tumor suppressor PTEN: modulator of cell signaling, growth, migration and apoptosis. J. Cell Sci. 114: 2375-2382 [Abstract] [Full Text]  
• Gimm, O., Attie-Bitach, T., Lees, J. A., Vekemans, M., Eng, C. (2000). Expression of the PTEN tumour suppressor protein during human development. Hum Mol Genet 9: 1633-1639 [Abstract] [Full Text]  
• R.-BORLADO, L., REDONDO, C., ALVAREZ, B., JIMENEZ, C., CRIADO, L. M., FLORES, J., MARCOS, M. A. R., MARTINEZ-A, C., BALOMENOS, D., CARRERA, A. C. (2000). Increased phosphoinositide 3-kinase activity induces a lymphoproliferative disorder and contributes to tumor generation in vivo. FASEB J. 14: 895-903 [Abstract] [Full Text]  
• Gimm, O., Perren, A., Weng, L.-P., Marsh, D. J., Yeh, J. J., Ziebold, U., Gil, E., Hinze, R., Delbridge, L., Lees, J. A., Mutter, G. L., Robinson, B. G., Komminoth, P., Dralle, H., Eng, C. (2000). Differential Nuclear and Cytoplasmic Expression of PTEN in Normal Thyroid Tissue, and Benign and Malignant Epithelial Thyroid Tumors. Am. J. Pathol. 156: 1693-1700 [Abstract] [Full Text]  
• Zhang, P., Steinberg, B. M. (2000). Overexpression of PTEN/MMAC1 and Decreased Activation of Akt in Human Papillomavirus-infected Laryngeal Papillomas. Cancer Res. 60: 1457-1462 [Abstract] [Full Text]  
• Attur, M. G., Dave, M. N., Clancy, R. M., Patel, I. R., Abramson, S. B., Amin, A. R. (2000). Functional Genomic Analysis in Arthritis-Affected Cartilage: Yin-Yang Regulation of Inflammatory Mediators by {alpha}5{beta}1 and {alpha}V{beta}3 Integrins. J. Immunol. 164: 2684-2691 [Abstract] [Full Text]  
• Lachyankar, M. B., Sultana, N., Schonhoff, C. M., Mitra, P., Poluha, W., Lambert, S., Quesenberry, P. J., Litofsky, N. S., Recht, L. D., Nabi, R., Miller, S. J., Ohta, S., Neel, B. G., Ross, A. H. (2000). A Role for Nuclear PTEN in Neuronal Differentiation. J. Neurosci. 20: 1404-1413 [Abstract] [Full Text]  
• Adey, N. B., Huang, L., Ormonde, P. A., Baumgard, M. L., Pero, R., Byreddy, D. V., Tavtigian, S. V., Bartel, P. L. (2000). Threonine Phosphorylation of the MMAC1/PTEN PDZ Binding Domain Both Inhibits and Stimulates PDZ Binding. Cancer Res. 60: 35-37 [Abstract] [Full Text]  
• Akamatsu, M., Aota, S.-i., Suwa, A., Ueda, K., Amachi, T., Yamada, K. M., Akiyama, S. K., Kioka, N. (1999). Vinexin Forms a Signaling Complex with Sos and Modulates Epidermal Growth Factor-induced c-Jun N-terminal Kinase/Stress-activated Protein Kinase Activities. J. Biol. Chem. 274: 35933-35937 [Abstract] [Full Text]  
• Datta, S. R., Brunet, A., Greenberg, M. E. (1999). Cellular survival: a play in three Akts. Genes Dev. 13: 2905-2927 [Full Text]  
• Tamura, M., Gu, J., Tran, H., Yamada, K. M. (1999). PTEN Gene and Integrin Signaling in Cancer. JNCI J Natl Cancer Inst 91: 1820-1828 [Abstract] [Full Text]  
• McMenamin, M. E., Soung, P., Perera, S., Kaplan, I., Loda, M., Sellers, W. R. (1999). Loss of PTEN Expression in Paraffin-embedded Primary Prostate Cancer Correlates with High Gleason Score and Advanced Stage. Cancer Res. 59: 4291-4296 [Abstract] [Full Text]  
• Giancotti, F. G., Ruoslahti, E. (1999). Integrin Signaling. Science 285: 1028-1033 [Abstract] [Full Text]  
• Gu, J., Tamura, M., Pankov, R., Danen, E. H.J., Takino, T., Matsumoto, K., Yamada, K. M. (1999). Shc and FAK Differentially Regulate Cell Motility and Directionality Modulated by PTEN. J. Cell Biol. 146: 389-404 [Abstract] [Full Text]  
• Tamura, M., Gu, J., Danen, E. H. J., Takino, T., Miyamoto, S., Yamada, K. M. (1999). PTEN Interactions with Focal Adhesion Kinase and Suppression of the Extracellular Matrix-dependent Phosphatidylinositol 3-Kinase/Akt Cell Survival Pathway. J. Biol. Chem. 274: 20693-20703 [Abstract] [Full Text]  
• Mihaylova, V. T., Borland, C. Z., Manjarrez, L., Stern, M. J., Sun, H. (1999). The PTEN tumor suppressor homolog in Caenorhabditis elegans regulates longevity and dauer formation in an insulin receptor-like signaling pathway. Proc. Natl. Acad. Sci. USA 96: 7427-7432 [Abstract] [Full Text]  
• Cheney, I. W., Neuteboom, S. T. C., Vaillancourt, M.-T., Ramachandra, M., Bookstein, R. (1999). Adenovirus-mediated Gene Transfer of MMAC1/PTEN to Glioblastoma Cells Inhibits S Phase Entry by the Recruitment of p27Kip1 into Cyclin E/CDK2 Complexes. Cancer Res. 59: 2318-2323 [Abstract] [Full Text]  
• Tamura, M., Gu, J., Takino, T., Yamada, K. M. (1999). Tumor Suppressor PTEN Inhibition of Cell Invasion, Migration, and Growth: Differential Involvement of Focal Adhesion Kinase and p130Cas. Cancer Res. 59: 442-449 [Abstract] [Full Text]  
• Escalante, M., Courtney, J., Chin, W. G., Teng, K. K., Kim, J.-I., Fajardo, J. E., Mayer, B. J., Hempstead, B. L., Birge, R. B. (2000). Phosphorylation of c-Crk II on the Negative Regulatory Tyr222 Mediates Nerve Growth Factor-induced Cell Spreading and Morphogenesis. J. Biol. Chem. 275: 24787-24797 [Abstract] [Full Text]  
• Kawano, Y., Okamoto, I., Murakami, D., Itoh, H., Yoshida, M., Ueda, S., Saya, H. (2000). Ras Oncoprotein Induces CD44 Cleavage through Phosphoinositide 3-OH Kinase and the Rho Family of Small G Proteins. J. Biol. Chem. 275: 29628-29635 [Abstract] [Full Text]  
• Yart, A., Laffargue, M., Mayeux, P., Chretien, S., Peres, C., Tonks, N., Roche, S., Payrastre, B., Chap, H., Raynal, P. (2001). A Critical Role for Phosphoinositide 3-Kinase Upstream of Gab1 and SHP2 in the Activation of Ras and Mitogen-activated Protein Kinases by Epidermal Growth Factor. J. Biol. Chem. 276: 8856-8864 [Abstract] [Full Text]  
• Koul, D., Yao, Y., Abbruzzese, J. L., Yung, W. K. A., Reddy, S. A. G. (2001). Tumor Suppressor MMAC/PTEN Inhibits Cytokine-induced NFkappa B Activation without Interfering with the Ikappa B Degradation Pathway. J. Biol. Chem. 276: 11402-11408 [Abstract] [Full Text]  
• Wu, Y., Dowbenko, D., Spencer, S., Laura, R., Lee, J., Gu, Q., Lasky, L. A. (2000). Interaction of the Tumor Suppressor PTEN/MMAC with a PDZ Domain of MAGI3, a Novel Membrane-associated Guanylate Kinase. J. Biol. Chem. 275: 21477-21485 [Abstract] [Full Text]  
• Persad, S., Attwell, S., Gray, V., Delcommenne, M., Troussard, A., Sanghera, J., Dedhar, S. (2000). Inhibition of integrin-linked kinase (ILK) suppresses activation of protein kinase B/Akt and induces cell cycle arrest and apoptosis of PTEN-mutant prostate cancer cells. Proc. Natl. Acad. Sci. USA 97: 3207-3212 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents