This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by van Weering, D. H. J.
Right arrow Articles by Burgering, B. M. T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by van Weering, D. H. J.
Right arrow Articles by Burgering, B. M. T.

 Previous Article  |  Next Article 

Mol Cell Biol, April 1998, p. 1802-1811, Vol. 18, No. 4
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Protein Kinase B Activation and Lamellipodium Formation Are Independent Phosphoinositide 3-Kinase-Mediated Events Differentially Regulated by Endogenous Ras

David H. J. van Weering,1 Johan de Rooij,1 Barbara Marte,2 Julian Downward,2 Johannes L. Bos,1 and Boudewijn M. T. Burgering1,*

Laboratory for Physiological Chemistry, Utrecht University, Utrecht, The Netherlands,1 and Imperial Cancer Research Funds, Fields, London, United Kingdom2

Received 8 August 1997/Returned for modification 9 September 1997/Accepted 16 December 1997

Regulation of phosphoinositide 3-kinase (PI 3-kinase) can occur by binding of the regulatory p85 subunit to tyrosine-phosphorylated proteins and by binding of the p110 catalytic subunit to activated Ras. However, the way in which these regulatory mechanisms act to regulate PI 3-kinase in vivo is unclear. Here we show that several growth factors (basic fibroblast growth factor [bFGF], platelet-derived growth factor [PDGF], and epidermal growth factor [EGF; to activate an EGF receptor-Ret chimeric receptor]) all activate PI 3-kinase in vivo in the neuroectoderm-derived cell line SKF5. However, these growth factors differ in their ability to activate PI 3-kinase-dependent signaling. PDGF and EGF(Ret) treatment induced PI 3-kinase-dependent lamellipodium formation and protein kinase B (PKB) activation. In contrast, bFGF did not induce lamellipodium formation but activated PKB, albeit to a small extent. PDGF and EGF(Ret) stimulation resulted in binding of p85 to tyrosine-phosphorylated proteins and strong Ras activation. bFGF, however, induced only strong activation of Ras. In addition, while RasAsn17 abolished bFGF activation of PKB, PDGF- and EGF(Ret)-induced PKB activation was only partially inhibited and lamellipodium formation was unaffected. Interestingly, in contrast to activation of only endogenous Ras (bFGF), ectopic expression of activated Ras did result in lamellipodium formation. From this we conclude that, in vivo, p85 and Ras synergize to activate PI 3-kinase and that strong activation of only endogenous Ras exerts a small effect on PI 3-kinase activity, sufficient for PKB activation but not lamellipodium formation. This differential sensitivity to PI 3-kinase activation could be explained by our finding that PKB activation and lamellipodium formation are independent PI 3-kinase-induced events.

* Corresponding author. Mailing address: Laboratory for Physiological Chemistry, Utrecht University, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands. Phone: 31-30-2538918. Fax: 31-30-2539035. E-mail: b.m.t.burgering{at}med.ruu.nl.




This article has been cited by other articles:

  • Basu, S., Ray, N. T., Atkinson, S. J., Broxmeyer, H. E. (2007). Protein Phosphatase 2A Plays an Important Role in Stromal Cell-Derived Factor-1/CXC Chemokine Ligand 12-Mediated Migration and Adhesion of CD34+ Cells. J. Immunol. 179: 3075-3085 [Abstract] [Full Text]  
  • Carloni, V., Vizzutti, F., Pantaleo, P. (2005). Farnesyltransferase Inhibitor, ABT-100, Is a Potent Liver Cancer Chemopreventive Agent. Clin. Cancer Res. 11: 4266-4274 [Abstract] [Full Text]  
  • Gonzalez-Martinez, D., Kim, S.-H., Hu, Y., Guimond, S., Schofield, J., Winyard, P., Vannelli, G. B., Turnbull, J., Bouloux, P.-M. (2004). Anosmin-1 Modulates Fibroblast Growth Factor Receptor 1 Signaling in Human Gonadotropin-Releasing Hormone Olfactory Neuroblasts through a Heparan Sulfate-Dependent Mechanism. J. Neurosci. 24: 10384-10392 [Abstract] [Full Text]  
  • Hu, Y., Fang, X., Dunham, S. M., Prada, C., Stachowiak, E. K., Stachowiak, M. K. (2004). 90-kDa Ribosomal S6 Kinase Is a Direct Target for the Nuclear Fibroblast Growth Factor Receptor 1 (FGFR1): ROLE IN FGFR1 SIGNALING. J. Biol. Chem. 279: 29325-29335 [Abstract] [Full Text]  
  • Perrini, S., Natalicchio, A., Laviola, L., Belsanti, G., Montrone, C., Cignarelli, A., Minielli, V., Grano, M., De Pergola, G., Giorgino, R., Giorgino, F. (2004). Dehydroepiandrosterone Stimulates Glucose Uptake in Human and Murine Adipocytes by Inducing GLUT1 and GLUT4 Translocation to the Plasma Membrane. Diabetes 53: 41-52 [Abstract] [Full Text]  
  • Liu, S., Premont, R. T., Kontos, C. D., Huang, J., Rockey, D. C. (2003). Endothelin-1 Activates Endothelial Cell Nitric-oxide Synthase via Heterotrimeric G-protein {beta}{gamma} Subunit Signaling to Protein Kinase B/Akt. J. Biol. Chem. 278: 49929-49935 [Abstract] [Full Text]  
  • Gorin, Y., Ricono, J. M., Kim, N.-H., Bhandari, B., Choudhury, G. G., Abboud, H. E. (2003). Nox4 mediates angiotensin II-induced activation of Akt/protein kinase B in mesangial cells. Am. J. Physiol. Renal Physiol. 285: F219-F229 [Abstract] [Full Text]  
  • Guo, F., Gao, Y., Wang, L., Zheng, Y. (2003). p19Arf-p53 Tumor Suppressor Pathway Regulates Cell Motility by Suppression of Phosphoinositide 3-Kinase and Rac1 GTPase Activities. J. Biol. Chem. 278: 14414-14419 [Abstract] [Full Text]  
  • Jacob, A., Cooney, D., Pradhan, M., Coggeshall, K. M. (2002). Convergence of Signaling Pathways on the Activation of ERK in B Cells. J. Biol. Chem. 277: 23420-23426 [Abstract] [Full Text]  
  • Lu, L., Holmqvist, K., Cross, M., Welsh, M. (2002). Role of the Src Homology 2 Domain-containing Protein Shb in Murine Brain Endothelial Cell Proliferation and Differentiation. Cell Growth Differ. 13: 141-148 [Abstract] [Full Text]  
  • Mochizuki, Y., Nakamura, T., Kanetake, H., Kanda, S. (2002). Angiopoietin 2 stimulates migration and tube-like structure formation of murine brain capillary endothelial cells through c-Fes and c-Fyn. J. Cell Sci. 115: 175-183 [Abstract] [Full Text]  
  • Abreu, M. T., Arnold, E. T., Chow, J. Y. C., Barrett, K. E. (2001). Phosphatidylinositol 3-Kinase-dependent Pathways Oppose Fas-induced Apoptosis and Limit Chloride Secretion in Human Intestinal Epithelial Cells. IMPLICATIONS FOR INFLAMMATORY DIARRHEAL STATES. J. Biol. Chem. 276: 47563-47574 [Abstract] [Full Text]  
  • Todisco, A., Pausawasdi, N., Ramamoorthy, S., Del Valle, J., Van Dyke, R. W., Askari, F. K. (2001). Functional Role of Protein Kinase B/Akt in Gastric Acid Secretion. J. Biol. Chem. 276: 46436-46444 [Abstract] [Full Text]  
  • Hennige, A. M., Lammers, R., Hoppner, W., Arlt, D., Strack, V., Teichmann, R., Machicao, F., Ullrich, A., Haring, H.-U., Kellerer, M. (2001). Inhibition of Ret Oncogene Activity by the Protein Tyrosine Phosphatase SHP1. Endocrinology 142: 4441-4447 [Abstract] [Full Text]  
  • Ng, S. S. W., Tsao, M.-S., Nicklee, T., Hedley, D. W. (2001). Wortmannin Inhibits PKB/Akt Phosphorylation and Promotes Gemcitabine Antitumor Activity in Orthotopic Human Pancreatic Cancer Xenografts in Immunodeficient Mice. Clin. Cancer Res. 7: 3269-3275 [Abstract] [Full Text]  
  • Bahuau, M., Pelet, A., Vidaud, D., Lamireau, T., Le Bail, B., Munnich, A., Vidaud, M., Lyonnet, S., Lacombe, D. (2001). GDNF as a candidate modifier in a type 1 neurofibromatosis (NF1) enteric phenotype. J. Med. Genet. 38: 638-643 [Full Text]  
  • Vale, T., Ngo, T. T., White, M. A., Lipsky, P. E. (2001). Raf-induced Transformation Requires an Interleukin 1 Autocrine Loop. Cancer Res. 61: 602-607 [Abstract] [Full Text]  
  • Carballada, R, Yasuo, H, Lemaire, P (2001). Phosphatidylinositol-3 kinase acts in parallel to the ERK MAP kinase in the FGF pathway during Xenopus mesoderm induction. Development 128: 35-44 [Abstract]  
  • Hansford, J. R, Mulligan, L. M (2000). Multiple endocrine neoplasia type 2 and RET: from neoplasia to neurogenesis. J. Med. Genet. 37: 817-827 [Abstract] [Full Text]  
  • Ng, S. S. W., Tsao, M.-S., Chow, S., Hedley, D. W. (2000). Inhibition of Phosphatidylinositide 3-Kinase Enhances Gemcitabine-induced Apoptosis in Human Pancreatic Cancer Cells. Cancer Res. 60: 5451-5455 [Abstract] [Full Text]  
  • Genot, E. M., Arrieumerlou, C., Ku, G., Burgering, B. M. T., Weiss, A., Kramer, I. M. (2000). The T-Cell Receptor Regulates Akt (Protein Kinase B) via a Pathway Involving Rac1 and Phosphatidylinositide 3-Kinase. Mol. Cell. Biol. 20: 5469-5478 [Abstract] [Full Text]  
  • Gabriella De Vita, , Melillo, R. M., Carlomagno, F., Visconti, R., Castellone, M. D., Bellacosa, A., Billaud, M., Fusco, A., Tsichlis, P. N., Santoro, M. (2000). Tyrosine 1062 of RET-MEN2A Mediates Activation of Akt (Protein Kinase B) and Mitogen-activated Protein Kinase Pathways Leading to PC12 Cell Survival. Cancer Res. 60: 3727-3731 [Abstract] [Full Text]  
  • Klingenberg, O., Wiedlocha, A., Citores, L., Olsnes, S. (2000). Requirement of Phosphatidylinositol 3-Kinase Activity for Translocation of Exogenous aFGF to the Cytosol and Nucleus. J. Biol. Chem. 275: 11972-11980 [Abstract] [Full Text]  
  • Kainulainen, V., Sundvall, M., Maatta, J. A., Santiestevan, E., Klagsbrun, M., Elenius, K. (2000). A Natural ErbB4 Isoform That Does Not Activate Phosphoinositide 3-Kinase Mediates Proliferation but Not Survival or Chemotaxis. J. Biol. Chem. 275: 8641-8649 [Abstract] [Full Text]  
  • Segouffin-Cariou, C., Billaud, M. (2000). Transforming Ability of MEN2A-RET Requires Activation of the Phosphatidylinositol 3-Kinase/AKT Signaling Pathway. J. Biol. Chem. 275: 3568-3576 [Abstract] [Full Text]  
  • Cross, M., Hodgkin, M., Roberts, S, Landgren, E, Wakelam, M., Claesson-Welsh, L (2000). Tyrosine 766 in the fibroblast growth factor receptor-1 is required for FGF-stimulation of phospholipase C, phospholipase D, phospholipase A(2), phosphoinositide 3-kinase and cytoskeletal reorganisation in porcine aortic endothelial cells. J. Cell Sci. 113: 643-651 [Abstract]  
  • Jiang, K., Coppola, D., Crespo, N. C., Nicosia, S. V., Hamilton, A. D., Sebti, S. M., Cheng, J. Q. (2000). The Phosphoinositide 3-OH Kinase/AKT2 Pathway as a Critical Target for Farnesyltransferase Inhibitor-Induced Apoptosis. Mol. Cell. Biol. 20: 139-148 [Abstract] [Full Text]  
  • Eguchi, S., Iwasaki, H., Ueno, H., Frank, G. D., Motley, E. D., Eguchi, K., Marumo, F., Hirata, Y., Inagami, T. (1999). Intracellular Signaling of Angiotensin II-induced p70 S6 Kinase Phosphorylation at Ser411 in Vascular Smooth Muscle Cells. POSSIBLE REQUIREMENT OF EPIDERMAL GROWTH FACTOR RECEPTOR, RAS, EXTRACELLULAR SIGNAL-REGULATED KINASE, AND AKT. J. Biol. Chem. 274: 36843-36851 [Abstract] [Full Text]  
  • Sotsios, Y., Whittaker, G. C., Westwick, J., Ward, S. G. (1999). The CXC Chemokine Stromal Cell-Derived Factor Activates a Gi-Coupled Phosphoinositide 3-Kinase in T Lymphocytes. J. Immunol. 163: 5954-5963 [Abstract] [Full Text]  
  • Cass, L. A., Summers, S. A., Prendergast, G. V., Backer, J. M., Birnbaum, M. J., Meinkoth, J. L. (1999). Protein Kinase A-Dependent and -Independent Signaling Pathways Contribute to Cyclic AMP-Stimulated Proliferation. Mol. Cell. Biol. 19: 5882-5891 [Abstract] [Full Text]  
  • Joneson, T., Bar-Sagi, D. (1999). Suppression of Ras-Induced Apoptosis by the Rac GTPase. Mol. Cell. Biol. 19: 5892-5901 [Abstract] [Full Text]  
  • Hitomi, M., Stacey, D. W. (1999). Cellular Ras and Cyclin D1 Are Required during Different Cell Cycle Periods in Cycling NIH 3T3 Cells. Mol. Cell. Biol. 19: 4623-4632 [Abstract] [Full Text]  
  • Wang, Q., Somwar, R., Bilan, P. J., Liu, Z., Jin, J., Woodgett, J. R., Klip, A. (1999). Protein Kinase B/Akt Participates in GLUT4 Translocation by Insulin in L6 Myoblasts. Mol. Cell. Biol. 19: 4008-4018 [Abstract] [Full Text]  
  • Wennstrom, S., Downward, J. (1999). Role of Phosphoinositide 3-Kinase in Activation of Ras and Mitogen-Activated Protein Kinase by Epidermal Growth Factor. Mol. Cell. Biol. 19: 4279-4288 [Abstract] [Full Text]  
  • Dufner, A., Andjelkovic, M., Burgering, B. M. T., Hemmings, B. A., Thomas, G. (1999). Protein Kinase B Localization and Activation Differentially Affect S6 Kinase 1 Activity and Eukaryotic Translation Initiation Factor 4E-Binding Protein 1 Phosphorylation. Mol. Cell. Biol. 19: 4525-4534 [Abstract] [Full Text]  
  • Law, B. K., Norgaard, P., Gnudi, L., Kahn, B. B., Poulson, H. S., Moses, H. L. (1999). Inhibition of DNA Synthesis by a Farnesyltransferase Inhibitor Involves Inhibition of the p70s6k Pathway. J. Biol. Chem. 274: 4743-4748 [Abstract] [Full Text]  
  • Besset, V., Scott, R. P., Ibanez, C. F. (2000). Signaling Complexes and Protein-Protein Interactions Involved in the Activation of the Ras and Phosphatidylinositol 3-Kinase Pathways by the c-Ret Receptor Tyrosine Kinase. J. Biol. Chem. 275: 39159-39166 [Abstract] [Full Text]  
  • Califano, D., Rizzo, C., D'Alessio, A., Colucci-D'Amato, G. L., Cali, G., Bartoli, P. C., Santelli, G., Vecchio, G., de Franciscis, V. (2000). Signaling through Ras Is Essential for ret Oncogene-induced Cell Differentiation in PC12 Cells. J. Biol. Chem. 275: 19297-19305 [Abstract] [Full Text]  
  • Yarwood, S. J., Woodgett, J. R. (2001). Extracellular matrix composition determines the transcriptional response to epidermal growth factor receptor activation. Proc. Natl. Acad. Sci. USA 98: 4472-4477 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»