Skip to main content
SpringerLink
Log in

Role of RAS in the Regulation of PI 3-Kinase

  • Chapter
  • First Online:
Phosphoinositide 3-kinase in Health and Disease

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 346))

Abstract

Ras proteins are key regulators of signalling cascades, controlling many processes such as proliferation, differentiation and apoptosis. Mutations in these proteins or in their effectors, activators and regulators are associated with pathological conditions, particularly the development of various forms of human cancer. RAS proteins signal through direct interaction with a number of effector enzymes, one of the best characterized being type I phosphatidylinositol (PI) 3-kinases. Although the ability of RAS to control PI 3-kinase has long been well established in cultured cells, evidence for a role of the interaction of endogenous RAS with PI 3-kinase in normal and malignant cell growth in vivo has only been obtained recently. Mice with mutations in the PI 3-kinase catalytic p110a isoform that block its ability to interact with RAS are highly resistant to endogenous KRAS oncogene induced lung tumourigenesis and HRAS oncogene induced skin carcinogenesis. Cells from these mice show proliferative defects and selective disruption of signalling from certain growth factors to PI 3-kinase, while the mice also display delayed development of the lymphatic vasculature. The interaction of RAS with p110a is thus required in vivo for some normal growth factor signalling and also for RAS-driven tumour formation.

RAS family members were among the first oncogenes identified over 40 years ago. In the late 1960s, the rat-derived Harvey and Kirsten murine sarcoma retroviruses were discovered and subsequently shown to promote cancer formation through related oncogenes, termed RAS (from rat sarcoma virus). The central role of RAS proteins in human cancer is highlighted by the large number of tumours in which they are activated by mutation: approximately 20% of human cancers carry a mutation in RAS proteins. Because of the complex signalling network in which RAS operates, with multiple activators and effectors, each with a different pattern of tissue-specific expression and a distinct set of intracellular functions, one of the critical issues concerns the specific role of each effector in RAS-driven oncogenesis. In this chapter, we summarize current knowledge about how RAS regulates one of its best-known effectors, phosphoinositide 3-kinase (PI3K).

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Auger KR et al (1989) PDGF-dependent tyrosine phosphorylation stimulates production of novel polyphosphoinositides in intact cells. Cell 57:167–175

    Article  PubMed  CAS  Google Scholar 

  • Avruch J et al (2001) Ras activation of the Raf kinase: tyrosine kinase recruitment of the MAP kinase cascade. Recent Prog Horm Res 56:127–155

    Article  PubMed  CAS  Google Scholar 

  • Ballif BA et al (2005) Quantitative phosphorylation profiling of the ERK/p90 ribosomal S6 kinase-signaling cassette and its targets, the tuberous sclerosis tumor suppressors. Proc Natl Acad Sci USA 102:667–672

    Article  PubMed  CAS  Google Scholar 

  • Barbacid M (1987) ras genes. Annu Rev Biochem 56:779–827

    Article  PubMed  CAS  Google Scholar 

  • Bar-Sagi D (2001) A Ras by any other name. Mol Cell Biol 21:1441–1443

    Article  PubMed  CAS  Google Scholar 

  • Benard V et al (1999) Characterization of rac and cdc42 activation in chemoattractant-stimulated human neutrophils using a novel assay for active GTPases. J Biol Chem 274:13198–13204

    Article  PubMed  CAS  Google Scholar 

  • Bos JL (1989) ras oncogenes in human cancer: a review. Cancer Res 49:4682–4689

    PubMed  CAS  Google Scholar 

  • Bourne HR et al (1990) The GTPase superfamily: a conserved switch for diverse cell functions. Nature 348:125–132

    Article  PubMed  CAS  Google Scholar 

  • Broach JR, Deschenes RJ (1990) The function of ras genes in Saccharomyces cerevisiae. Adv Cancer Res 54:79–139

    Article  PubMed  CAS  Google Scholar 

  • Brunet A et al (1999) Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96:857–868

    Article  PubMed  CAS  Google Scholar 

  • Burgering BM, Coffer PJ (1995) Protein kinase B (c-Akt) in phosphatidylinositol-3-OH kinase signal transduction. Nature 376:599–602

    Article  PubMed  CAS  Google Scholar 

  • Cacace AM et al (1999) Identification of constitutive and ras-inducible phosphorylation sites of KSR: implications for 14-3-3 binding, mitogen-activated protein kinase binding, and KSR overexpression. Mol Cell Biol 19:229–240

    PubMed  CAS  Google Scholar 

  • Campbell PM, Der CJ (2004) Oncogenic Ras and its role in tumor cell invasion and metastasis. Semin Cancer Biol 14:105–114

    Article  PubMed  CAS  Google Scholar 

  • Campbell PM et al (2007) K-Ras promotes growth transformation and invasion of immortalized human pancreatic cells by Raf and phosphatidylinositol 3-kinase signaling. Cancer Res 67:2098–2106

    Article  PubMed  CAS  Google Scholar 

  • Cancer Genome Atlas Research Network (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455:1061–1068

    Article  CAS  Google Scholar 

  • Cantley LC (2002) The phosphoinositide 3-kinase pathway. Science 296:1655–1657

    Article  PubMed  CAS  Google Scholar 

  • Carracedo A et al (2008) Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Invest 118:3065–3074

    PubMed  CAS  Google Scholar 

  • Chambers AF et al (2002) Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer 2:563–572

    Article  PubMed  CAS  Google Scholar 

  • Chan TO et al (2002) Small GTPases and tyrosine kinases coregulate a molecular switch in the phosphoinositide 3-kinase regulatory subunit. Cancer Cell 1:181–191

    Article  PubMed  CAS  Google Scholar 

  • Chang F et al (2003) Involvement of PI3K/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: a target for cancer chemotherapy. Leukemia 17:590–603

    Article  PubMed  CAS  Google Scholar 

  • Chiarugi P, Giannoni E (2008) Anoikis: a necessary death program for anchorage-dependent cells. Biochem Pharmacol 76:1352–1364

    Article  PubMed  CAS  Google Scholar 

  • Chin L et al (1999) Essential role for oncogenic Ras in tumour maintenance. Nature 400:468–472

    Article  PubMed  CAS  Google Scholar 

  • Choy E et al (1999) Endomembrane trafficking of ras: the CAAX motif targets proteins to the ER and Golgi. Cell 98:69–80

    Article  PubMed  CAS  Google Scholar 

  • Cichowski K, Jacks T (2001) NF1 tumor suppressor gene function: narrowing the GAP. Cell 104:593–604

    Article  PubMed  CAS  Google Scholar 

  • Cox AD, Der CJ (2003) The dark side of Ras: regulation of apoptosis. Oncogene 22:8999–9006

    Article  PubMed  CAS  Google Scholar 

  • Cozzolino M et al (2003) p120 Catenin is required for growth factor-dependent cell motility and scattering in epithelial cells. Mol Biol Cell 14:1964–1977

    Article  PubMed  CAS  Google Scholar 

  • Crews CM, Erikson RL (1993) Extracellular signals and reversible protein phosphorylation: what to Mek of it all. Cell 74:215–217

    Article  PubMed  CAS  Google Scholar 

  • D'Adamo DR et al (1997) rsc: a novel oncogene with structural and functional homology with the gene family of exchange factors for Ral. Oncogene 14:1295–1305

    Article  PubMed  Google Scholar 

  • Dai Q et al (1998) Mammalian prenylcysteine carboxyl methyltransferase is in the endoplasmic reticulum. J Biol Chem 273:15030–15034

    Article  PubMed  CAS  Google Scholar 

  • Datta SR et al (1997) Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91:231–241

    Article  PubMed  CAS  Google Scholar 

  • Davies H et al (2002) Mutations of the BRAF gene in human cancer. Nature 417:949–954

    Article  PubMed  CAS  Google Scholar 

  • Djordjevic S, Driscoll PC (2002) Structural insight into substrate specificity and regulatory mechanisms of phosphoinositide 3-kinases. Trends Biochem Sci 27:426–432

    Article  PubMed  CAS  Google Scholar 

  • Downward J (1998) Ras signalling and apoptosis. Curr Opin Genet Dev 8:49–54

    Article  PubMed  CAS  Google Scholar 

  • Downward J (2003) Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer 3:11–22

    Article  PubMed  CAS  Google Scholar 

  • Downward J (2004) PI 3-kinase, Akt and cell survival. Semin Cell Dev Biol 15:177–182

    Article  PubMed  CAS  Google Scholar 

  • Duffy MJ et al (2008) Cancer invasion and metastasis: changing views. J Pathol 214:283–293

    Article  PubMed  CAS  Google Scholar 

  • Ehrhardt A et al (2002) Ras and relatives–job sharing and networking keep an old family together. Exp Hematol 30:1089–1106

    Article  PubMed  CAS  Google Scholar 

  • Ehrhardt A et al (2004) Distinct mechanisms determine the patterns of differential activation of H-Ras, N-Ras, K-Ras 4B, and M-Ras by receptors for growth factors or antigen. Mol Cell Biol 24:6311–6323

    Article  PubMed  CAS  Google Scholar 

  • Engelman JA et al (2008) Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat Med 14:1351–1356

    Article  PubMed  CAS  Google Scholar 

  • Etienne-Manneville S, Hall A (2002) Rho GTPases in cell biology. Nature 420:629–635

    Article  PubMed  CAS  Google Scholar 

  • Fabian JR et al (1994) A single amino acid change in Raf-1 inhibits Ras binding and alters Raf-1 function. Proc Natl Acad Sci USA 91:5982–5986

    Article  PubMed  CAS  Google Scholar 

  • Field J et al (1987) Guanine nucleotide activation of, and competition between, RAS proteins from Saccharomyces cerevisiae. Mol Cell Biol 7:2128–2133

    PubMed  CAS  Google Scholar 

  • Fisher GH et al (2001) Induction and apoptotic regression of lung adenocarcinomas by regulation of a K-Ras transgene in the presence and absence of tumor suppressor genes. Genes Dev 15:3249–3262

    Article  PubMed  CAS  Google Scholar 

  • Frisch SM et al (1996) Control of adhesion-dependent cell survival by focal adhesion kinase. J Cell Biol 134:793–799

    Article  PubMed  CAS  Google Scholar 

  • Garcia-Echeverria C (2009) Protein and lipid kinase inhibitors as targeted anticancer agents of the Ras/Raf/MEK and PI3K/PKB pathways. Purinergic Signal 5:117–125

    Article  PubMed  CAS  Google Scholar 

  • Genot EM et al (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

    Article  PubMed  CAS  Google Scholar 

  • Giehl K (2005) Oncogenic Ras in tumour progression and metastasis. Biol Chem 386:193–205

    PubMed  CAS  Google Scholar 

  • Gille H, Downward J (1999) Multiple ras effector pathways contribute to G(1) cell cycle progression. J Biol Chem 274:22033–22040

    Article  PubMed  CAS  Google Scholar 

  • Gire V et al (2000) PI-3-kinase is an essential anti-apoptotic effector in the proliferative response of primary human epithelial cells to mutant RAS. Oncogene 19:2269–2276

    Article  PubMed  CAS  Google Scholar 

  • Giuriato S et al (2004) Conditional animal models: a strategy to define when oncogenes will be effective targets to treat cancer. Semin Cancer Biol 14:3–11

    Article  PubMed  CAS  Google Scholar 

  • Gonzalez-Garcia A et al (2005) RalGDS is required for tumor formation in a model of skin carcinogenesis. Cancer Cell 7:219–226

    Article  PubMed  CAS  Google Scholar 

  • Gupta S et al (2007) Binding of ras to phosphoinositide 3-kinase p110alpha is required for ras-driven tumorigenesis in mice. Cell 129:957–968

    Article  PubMed  CAS  Google Scholar 

  • Hall BE et al (2001) Structure-based mutagenesis reveals distinct functions for Ras switch 1 and switch 2 in Sos-catalyzed guanine nucleotide exchange. J Biol Chem 276:27629–27637

    Article  PubMed  CAS  Google Scholar 

  • Hamad NM et al (2002) Distinct requirements for Ras oncogenesis in human versus mouse cells. Genes Dev 16:2045–2057

    Article  PubMed  CAS  Google Scholar 

  • Hamilton M, Wolfman A (1998) Oncogenic Ha-Ras-dependent mitogen-activated protein kinase activity requires signaling through the epidermal growth factor receptor. J Biol Chem 273:28155–28162

    Article  PubMed  CAS  Google Scholar 

  • Han J et al (1998) Role of substrates and products of PI 3-kinase in regulating activation of Rac-related guanosine triphosphatases by Vav. Science 279:558–560

    Article  PubMed  CAS  Google Scholar 

  • Hancock JF (2003) Ras proteins: different signals from different locations. Nat Rev Mol Cell Biol 4:373–384

    Article  PubMed  CAS  Google Scholar 

  • Hancock JF et al (1989) All ras proteins are polyisoprenylated but only some are palmitoylated. Cell 57:1167–1177

    Article  PubMed  CAS  Google Scholar 

  • Hennessy BT et al (2005) Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat Rev Drug Discov 4:988–1004

    Article  PubMed  CAS  Google Scholar 

  • Herrmann C (2003) Ras-effector interactions: after one decade. Curr Opin Struct Biol 13:122–129

    Article  PubMed  CAS  Google Scholar 

  • Hirakawa T, Ruley HE (1988) Rescue of cells from ras oncogene-induced growth arrest by a second, complementing, oncogene. Proc Natl Acad Sci USA 85:1519–1523

    Article  PubMed  CAS  Google Scholar 

  • Huang L et al (1998) Structural basis for the interaction of Ras with RalGDS. Nat Struct Biol 5:422–426

    Article  PubMed  CAS  Google Scholar 

  • Ikenoue T et al (2005) Functional analysis of PIK3CA gene mutations in human colorectal cancer. Cancer Res 65:4562–4567

    Article  PubMed  CAS  Google Scholar 

  • Inoki K et al (2002) TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol 4:648–657

    Article  PubMed  CAS  Google Scholar 

  • Irani K et al (1997) Mitogenic signaling mediated by oxidants in Ras-transformed fibroblasts. Science 275:1649–1652

    Article  PubMed  CAS  Google Scholar 

  • Isakoff SJ et al (2005) Breast cancer-associated PIK3CA mutations are oncogenic in mammary epithelial cells. Cancer Res 65:10992–11000

    Article  PubMed  CAS  Google Scholar 

  • Jackson EL et al (2001) Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras. Genes Dev 15:3243–3248

    Article  PubMed  CAS  Google Scholar 

  • Jia S et al (2008) Essential roles of PI(3)K-p110beta in cell growth, metabolism and tumorigenesis. Nature 454:776–779

    PubMed  CAS  Google Scholar 

  • Jia S et al (2009) Should individual PI3 kinase isoforms be targeted in cancer? Curr Opin Cell Biol 21:199–208

    Article  PubMed  CAS  Google Scholar 

  • Jiang K et al (2004) Akt mediates Ras downregulation of RhoB, a suppressor of transformation, invasion, and metastasis. Mol Cell Biol 24:5565–5576

    Article  PubMed  CAS  Google Scholar 

  • Johnson L et al (2001) Somatic activation of the K-ras oncogene causes early onset lung cancer in mice. Nature 410:1111–1116

    Article  PubMed  CAS  Google Scholar 

  • Jones SM et al (1999) PDGF induces an early and a late wave of PI 3-kinase activity, and only the late wave is required for progression through G1. Curr Biol 9:512–521

    Article  PubMed  CAS  Google Scholar 

  • Kang S et al (2005) Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic. Proc Natl Acad Sci USA 102:802–807

    Article  PubMed  CAS  Google Scholar 

  • Karkkainen MJ et al (2004) Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins. Nat Immunol 5:74–80

    Article  PubMed  CAS  Google Scholar 

  • Khokhlatchev AV et al (1998) Phosphorylation of the MAP kinase ERK2 promotes its homodimerization and nuclear translocation. Cell 93:605–615

    Article  PubMed  CAS  Google Scholar 

  • Khwaja A et al (1997) Matrix adhesion and Ras transformation both activate a phosphoinositide 3-OH kinase and protein kinase B/Akt cellular survival pathway. EMBO J 16:2783–2793

    Article  PubMed  CAS  Google Scholar 

  • Kim E et al (1999) Disruption of the mouse Rce1 gene results in defective Ras processing and mislocalization of Ras within cells. J Biol Chem 274:8383–8390

    Article  PubMed  CAS  Google Scholar 

  • Kim D et al (2001) Akt/PKB promotes cancer cell invasion via increased motility and metalloproteinase production. FASEB J 15:1953–1962

    Article  PubMed  CAS  Google Scholar 

  • Kinkade CW et al (2008) Targeting AKT/mTOR and ERK MAPK signaling inhibits hormone-refractory prostate cancer in a preclinical mouse model. J Clin Invest 118:3051–3064

    PubMed  CAS  Google Scholar 

  • Kodaki T et al (1994) The activation of phosphatidylinositol 3-kinase by Ras. Curr Biol 4:798–806

    Article  PubMed  CAS  Google Scholar 

  • Land H et al (1983a) Tumorigenic conversion of primary embryo fibroblasts requires at least two cooperating oncogenes. Nature 304:596–602

    Article  PubMed  CAS  Google Scholar 

  • Land H et al (1983b) Cellular oncogenes and multistep carcinogenesis. Science 222:771–778

    Article  PubMed  CAS  Google Scholar 

  • Laprise P et al (2004) Down-regulation of MEK/ERK signaling by E-cadherin-dependent PI3K/Akt pathway in differentiating intestinal epithelial cells. J Cell Physiol 199:32–39

    Article  PubMed  CAS  Google Scholar 

  • Leon J et al (1987) Differential expression of the ras gene family in mice. Mol Cell Biol 7:1535–1540

    PubMed  CAS  Google Scholar 

  • Li W et al (2000) The leucine-rich repeat protein SUR-8 enhances MAP kinase activation and forms a complex with Ras and Raf. Genes Dev 14:895–900

    PubMed  CAS  Google Scholar 

  • Li W et al (2004) Transformation potential of Ras isoforms correlates with activation of phosphatidylinositol 3-kinase but not ERK. J Biol Chem 279:37398–37406

    Article  PubMed  CAS  Google Scholar 

  • Lim KH, Counter CM (2005) Reduction in the requirement of oncogenic Ras signaling to activation of PI3K/AKT pathway during tumor maintenance. Cancer Cell 8:381–392

    Article  PubMed  CAS  Google Scholar 

  • Lim KH et al (2005) Activation of RalA is critical for Ras-induced tumorigenesis of human cells. Cancer Cell 7:533–545

    Article  PubMed  CAS  Google Scholar 

  • Lim KH et al (2008) Tumour maintenance is mediated by eNOS. Nature 452:646–649

    Article  PubMed  CAS  Google Scholar 

  • Lin AW et al (1998) Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling. Genes Dev 12:3008–3019

    Article  PubMed  CAS  Google Scholar 

  • Lowy DR, Willumsen BM (1989) Protein modification: new clue to Ras lipid glue. Nature 341:384–385

    Article  PubMed  CAS  Google Scholar 

  • Lowy DR, Willumsen BM (1993) Function and regulation of ras. Annu Rev Biochem 62:851–891

    Article  PubMed  CAS  Google Scholar 

  • Lyons JF et al (2001) Discovery of a novel Raf kinase inhibitor. Endocr Relat Cancer 8:219–225

    Article  PubMed  CAS  Google Scholar 

  • Ma J, Karplus M (1997) Molecular switch in signal transduction: reaction paths of the conformational changes in ras p21. Proc Natl Acad Sci USA 94:11905–11910

    Article  PubMed  CAS  Google Scholar 

  • Ma L et al (2005) Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Cell 121:179–193

    Article  PubMed  CAS  Google Scholar 

  • Maehama T, Dixon JE (1998) The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3, 4, 5-trisphosphate. J Biol Chem 273:13375–13378

    Article  PubMed  CAS  Google Scholar 

  • Maehama T et al (2001) PTEN and myotubularin: novel phosphoinositide phosphatases. Annu Rev Biochem 70:247–279

    Article  PubMed  CAS  Google Scholar 

  • Malliri A et al (2002) Mice deficient in the Rac activator Tiam1 are resistant to Ras-induced skin tumours. Nature 417:867–871

    Article  PubMed  CAS  Google Scholar 

  • Manning BD et al (2002) Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol Cell 10:151–162

    Article  PubMed  CAS  Google Scholar 

  • Marais R et al (1993) The SRF accessory protein Elk-1 contains a growth factor-regulated transcriptional activation domain. Cell 73:381–393

    Article  PubMed  CAS  Google Scholar 

  • Marais R et al (1995) Ras recruits Raf-1 to the plasma membrane for activation by tyrosine phosphorylation. EMBO J 14:3136–3145

    PubMed  CAS  Google Scholar 

  • Marais R et al (1998) Requirement of Ras-GTP-Raf complexes for activation of Raf-1 by protein kinase C. Science 280:109–112

    Article  PubMed  CAS  Google Scholar 

  • Matallanas D et al (2003) Differences on the inhibitory specificities of H-Ras, K-Ras, and N-Ras (N17) dominant negative mutants are related to their membrane microlocalization. J Biol Chem 278:4572–4581

    Article  PubMed  CAS  Google Scholar 

  • Matallanas D et al (2006) Distinct utilization of effectors and biological outcomes resulting from site-specific Ras activation: Ras functions in lipid rafts and Golgi complex are dispensable for proliferation and transformation. Mol Cell Biol 26:100–116

    Article  PubMed  CAS  Google Scholar 

  • Mayo MW et al (1997) Requirement of NF-kappaB activation to suppress p53-independent apoptosis induced by oncogenic Ras. Science 278:1812–1815

    Article  PubMed  CAS  Google Scholar 

  • Menges CW, McCance DJ (2008) Constitutive activation of the Raf-MAPK pathway causes negative feedback inhibition of Ras-PI3K-AKT and cellular arrest through the EphA2 receptor. Oncogene 27:2934–2940

    Article  PubMed  CAS  Google Scholar 

  • Miller KA et al (2009) Oncogenic Kras requires simultaneous PI3K signaling to induce ERK activation and transform thyroid epithelial cells in vivo. Cancer Res 69:3689–3694

    Article  PubMed  CAS  Google Scholar 

  • Moodie SA et al (1993) Complexes of Ras.GTP with Raf-1 and mitogen-activated protein kinase kinase. Science 260:1658–1661

    Article  PubMed  CAS  Google Scholar 

  • Morrison D (1994) 14-3-3: modulators of signaling proteins? Science 266:56–57

    Article  PubMed  CAS  Google Scholar 

  • Nassar N et al (1995) The 2.2 A crystal structure of the Ras-binding domain of the serine/threonine kinase c-Raf1 in complex with Rap1A and a GTP analogue. Nature 375:554–560

    Article  PubMed  CAS  Google Scholar 

  • Nguyen DX et al (2009) Metastasis: from dissemination to organ-specific colonization. Nat Rev Cancer 9:274–284

    Article  PubMed  CAS  Google Scholar 

  • Nimnual AS et al (1998) Coupling of Ras and Rac guanosine triphosphatases through the Ras exchanger Sos. Science 279:560–563

    Article  PubMed  CAS  Google Scholar 

  • Oda K et al (2008) PIK3CA cooperates with other phosphatidylinositol 3′-kinase pathway mutations to effect oncogenic transformation. Cancer Res 68:8127–8136

    Article  PubMed  CAS  Google Scholar 

  • Ong SH et al (2001) Stimulation of phosphatidylinositol 3-kinase by fibroblast growth factor receptors is mediated by coordinated recruitment of multiple docking proteins. Proc Natl Acad Sci USA 98:6074–6079

    Article  PubMed  CAS  Google Scholar 

  • O'Reilly KE et al (2006) mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 66:1500–1508

    Article  PubMed  CAS  Google Scholar 

  • Orme MH et al (2006) Input from Ras is required for maximal PI(3)K signalling in Drosophila. Nat Cell Biol 8:1298–1302

    Article  PubMed  CAS  Google Scholar 

  • Ozes ON et al (1999) NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase. Nature 401:82–85

    Article  PubMed  CAS  Google Scholar 

  • Pacold ME et al (2000) Crystal structure and functional analysis of Ras binding to its effector phosphoinositide 3-kinase gamma. Cell 103:931–943

    Article  PubMed  CAS  Google Scholar 

  • Park BK et al (2001) Akt1 induces extracellular matrix invasion and matrix metalloproteinase-2 activity in mouse mammary epithelial cells. Cancer Res 61:7647–7653

    PubMed  CAS  Google Scholar 

  • Parsons DW et al (2005) Colorectal cancer: mutations in a signalling pathway. Nature 436:792

    Article  PubMed  CAS  Google Scholar 

  • Parsons DW et al (2008) An integrated genomic analysis of human glioblastoma multiforme. Science 321:1807–1812

    Article  PubMed  CAS  Google Scholar 

  • Pawson T, Nash P (2003) Assembly of cell regulatory systems through protein interaction domains. Science 300:445–452

    Article  PubMed  CAS  Google Scholar 

  • Plowman SJ, Hancock JF (2005) Ras signaling from plasma membrane and endomembrane microdomains. Biochim Biophys Acta 1746:274–283

    Article  PubMed  CAS  Google Scholar 

  • Prior IA et al (2001) GTP-dependent segregation of H-ras from lipid rafts is required for biological activity. Nat Cell Biol 3:368–375

    Article  PubMed  CAS  Google Scholar 

  • Prober DA, Edgar BA (2002) Interactions between Ras1, dMyc, and dPI3K signaling in the developing Drosophila wing. Genes Dev 16:2286–2299

    Article  PubMed  CAS  Google Scholar 

  • Ramjaun AR, Downward J (2007) Ras and phosphoinositide 3-kinase: partners in development and tumorigenesis. Cell Cycle 6:2902–2905

    Article  PubMed  CAS  Google Scholar 

  • Rangarajan A, Weinberg RA (2003) Opinion: Comparative biology of mouse versus human cells: modelling human cancer in mice. Nat Rev Cancer 3:952–959

    Article  PubMed  CAS  Google Scholar 

  • Rangarajan A et al (2004) Species- and cell type-specific requirements for cellular transformation. Cancer Cell 6:171–183

    Article  PubMed  CAS  Google Scholar 

  • Rapp UR et al (1983) Structure and biological activity of v-raf, a unique oncogene transduced by a retrovirus. Proc Natl Acad Sci USA 80:4218–4222

    Article  PubMed  CAS  Google Scholar 

  • Repasky GA et al (2004) Renewing the conspiracy theory debate: does Raf function alone to mediate Ras oncogenesis? Trends Cell Biol 14:639–647

    Article  PubMed  CAS  Google Scholar 

  • Reusch HP et al (2001) Regulation of Raf by Akt controls growth and differentiation in vascular smooth muscle cells. J Biol Chem 276:33630–33637

    Article  PubMed  CAS  Google Scholar 

  • Rocks O et al (2005) An acylation cycle regulates localization and activity of palmitoylated Ras isoforms. Science 307:1746–1752

    Article  PubMed  CAS  Google Scholar 

  • Rodriguez-Viciana P, McCormick F (2005) RalGDS comes of age. Cancer Cell 7:205–206

    Article  PubMed  CAS  Google Scholar 

  • Rodriguez-Viciana P et al (1994) Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature 370:527–532

    Article  PubMed  CAS  Google Scholar 

  • Rodriguez-Viciana P et al (1996) Activation of phosphoinositide 3-kinase by interaction with Ras and by point mutation. EMBO J 15:2442–2451

    PubMed  CAS  Google Scholar 

  • Rodriguez-Viciana P et al (1997) Role of phosphoinositide 3-OH kinase in cell transformation and control of the actin cytoskeleton by Ras. Cell 89:457–467

    Article  PubMed  CAS  Google Scholar 

  • Rodriguez-Viciana P et al (2004) Signaling specificity by Ras family GTPases is determined by the full spectrum of effectors they regulate. Mol Cell Biol 24:4943–4954

    Article  PubMed  CAS  Google Scholar 

  • Rojas JM, Santos E (2002) ras genes and human cancer: different implications and different roles. Curr Genom 3:295–311

    Article  CAS  Google Scholar 

  • Romashkova JA, Makarov SS (1999) NF-kappaB is a target of AKT in anti-apoptotic PDGF signalling. Nature 401:86–90

    Article  PubMed  CAS  Google Scholar 

  • Rommel C et al (1999) Differentiation stage-specific inhibition of the Raf-MEK-ERK pathway by Akt. Science 286:1738–1741

    Article  PubMed  CAS  Google Scholar 

  • Roy S et al (1998) 14-3-3 facilitates Ras-dependent Raf-1 activation in vitro and in vivo. Mol Cell Biol 18:3947–3955

    PubMed  CAS  Google Scholar 

  • Roy S et al (1999) Dominant-negative caveolin inhibits H-Ras function by disrupting cholesterol-rich plasma membrane domains. Nat Cell Biol 1:98–105

    Article  PubMed  CAS  Google Scholar 

  • Rubio I et al (1997) Interaction of Ras with phosphoinositide 3-kinase gamma. Biochem J 326(Pt 3):891–895

    PubMed  CAS  Google Scholar 

  • Ruley HE (1983) Adenovirus early region 1A enables viral and cellular transforming genes to transform primary cells in culture. Nature 304:602–606

    Article  PubMed  CAS  Google Scholar 

  • Sahai E, Marshall CJ (2002) RHO-GTPases and cancer. Nat Rev Cancer 2:133–142

    Article  PubMed  Google Scholar 

  • Samuels Y et al (2004) High frequency of mutations of the PIK3CA gene in human cancers. Science 304:554

    Article  PubMed  CAS  Google Scholar 

  • Samuels Y et al (2005) Mutant PIK3CA promotes cell growth and invasion of human cancer cells. Cancer Cell 7:561–573

    Article  PubMed  CAS  Google Scholar 

  • Sasaki AT, Firtel RA (2006) Regulation of chemotaxis by the orchestrated activation of Ras, PI3K, and TOR. Eur J Cell Biol 85:873–895

    Article  PubMed  CAS  Google Scholar 

  • Satoh T et al (1987) Induction of neurite formation in PC12 cells by microinjection of proto-oncogenic Ha-ras protein preincubated with guanosine-5′-O-(3-thiotriphosphate). Mol Cell Biol 7:4553–4556

    PubMed  CAS  Google Scholar 

  • Schlessinger J (2002) Ligand-induced, receptor-mediated dimerization and activation of EGF receptor. Cell 110:669–672

    Article  PubMed  CAS  Google Scholar 

  • Schulze A et al (2001) Analysis of the transcriptional program induced by Raf in epithelial cells. Genes Dev 15:981–994

    Article  PubMed  CAS  Google Scholar 

  • Selfors LM et al (1998) soc-2 encodes a leucine-rich repeat protein implicated in fibroblast growth factor receptor signaling. Proc Natl Acad Sci USA 95:6903–6908

    Article  PubMed  CAS  Google Scholar 

  • Shah OJ et al (2004) Inappropriate activation of the TSC/Rheb/mTOR/S6K cassette induces IRS1/2 depletion, insulin resistance, and cell survival deficiencies. Curr Biol 14:1650–1656

    Article  PubMed  CAS  Google Scholar 

  • Shannon KM et al (1994) Loss of the normal NF1 allele from the bone marrow of children with type 1 neurofibromatosis and malignant myeloid disorders. N Engl J Med 330:597–601

    Article  PubMed  CAS  Google Scholar 

  • Shaw RJ, Cantley LC (2006) Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature 441:424–430

    Article  PubMed  CAS  Google Scholar 

  • Shaw LM et al (1997) Activation of phosphoinositide 3-OH kinase by the alpha6beta4 integrin promotes carcinoma invasion. Cell 91:949–960

    Article  PubMed  CAS  Google Scholar 

  • Shelton JG et al (2003) Effects of the RAF/MEK/ERK and PI3K/AKT signal transduction pathways on the abrogation of cytokine-dependence and prevention of apoptosis in hematopoietic cells. Oncogene 22:2478–2492

    Article  PubMed  CAS  Google Scholar 

  • Sheng H et al (2001) Akt/PKB activity is required for Ha-Ras-mediated transformation of intestinal epithelial cells. J Biol Chem 276:14498–14504

    PubMed  CAS  Google Scholar 

  • Shields JM et al (2000) Understanding Ras: ‘it ain't over ‘til it's over'. Trends Cell Biol 10:147–154

    Article  PubMed  CAS  Google Scholar 

  • Side L et al (1997) Homozygous inactivation of the NF1 gene in bone marrow cells from children with neurofibromatosis type 1 and malignant myeloid disorders. N Engl J Med 336:1713–1720

    Article  PubMed  CAS  Google Scholar 

  • Sieburth DS et al (1998) SUR-8, a conserved Ras-binding protein with leucine-rich repeats, positively regulates Ras-mediated signaling in C. elegans. Cell 94:119–130

    Article  PubMed  CAS  Google Scholar 

  • Simi L et al (2008) High-resolution melting analysis for rapid detection of KRAS, BRAF, and PIK3CA gene mutations in colorectal cancer. Am J Clin Pathol 130:247–253

    Article  PubMed  CAS  Google Scholar 

  • Simpson CD et al (2008) Anoikis resistance and tumor metastasis. Cancer Lett 272:177–185

    Article  PubMed  CAS  Google Scholar 

  • Sjolander A et al (1991) Association of p21ras with phosphatidylinositol 3-kinase. Proc Natl Acad Sci USA 88:7908–7912

    Article  PubMed  CAS  Google Scholar 

  • Solit DB et al (2006) BRAF mutation predicts sensitivity to MEK inhibition. Nature 439:358–362

    Article  PubMed  CAS  Google Scholar 

  • Stacey D, Kazlauskas A (2002) Regulation of Ras signaling by the cell cycle. Curr Opin Genet Dev 12:44–46

    Article  PubMed  CAS  Google Scholar 

  • Steeg PS (2006) Tumor metastasis: mechanistic insights and clinical challenges. Nat Med 12:895–904

    Article  PubMed  CAS  Google Scholar 

  • Stemke-Hale K et al (2008) An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. Cancer Res 68:6084–6091

    Article  PubMed  CAS  Google Scholar 

  • Sturgill TW et al (1988) Insulin-stimulated MAP-2 kinase phosphorylates and activates ribosomal protein S6 kinase II. Nature 334:715–718

    Article  PubMed  CAS  Google Scholar 

  • Su AI et al (2004) A gene atlas of the mouse and human protein-encoding transcriptomes. Proc Natl Acad Sci USA 101:6062–6067

    Article  PubMed  CAS  Google Scholar 

  • Suire S et al (2006) Gbetagammas and the Ras binding domain of p110gamma are both important regulators of PI(3)Kgamma signalling in neutrophils. Nat Cell Biol 8:1303–1309

    Article  PubMed  CAS  Google Scholar 

  • Takuwa N, Takuwa Y (1997) Ras activity late in G1 phase required for p27kip1 downregulation, passage through the restriction point, and entry into S phase in growth factor-stimulated NIH 3T3 fibroblasts. Mol Cell Biol 17:5348–5358

    PubMed  CAS  Google Scholar 

  • Taylor SJ, Shalloway D (1996) Cell cycle-dependent activation of Ras. Curr Biol 6:1621–1627

    Article  PubMed  CAS  Google Scholar 

  • Therrien M et al (1999) Functional analysis of CNK in RAS signaling. Proc Natl Acad Sci USA 96:13259–13263

    Article  PubMed  CAS  Google Scholar 

  • Thomas RK et al (2007) High-throughput oncogene mutation profiling in human cancer. Nat Genet 39:347–351

    Article  PubMed  CAS  Google Scholar 

  • Torbett NE et al (2008) A chemical screen in diverse breast cancer cell lines reveals genetic enhancers and suppressors of sensitivity to PI3K isoform-selective inhibition. Biochem J 415:97–110

    Article  PubMed  CAS  Google Scholar 

  • Trahey M, McCormick F (1987) A cytoplasmic protein stimulates normal N-ras p21 GTPase, but does not affect oncogenic mutants. Science 238:542–545

    Article  PubMed  CAS  Google Scholar 

  • Treisman R (1996) Regulation of transcription by MAP kinase cascades. Curr Opin Cell Biol 8:205–215

    Article  PubMed  CAS  Google Scholar 

  • Tsutsumi K et al (2009) Visualization of Ras-PI3K interaction in the endosome using BiFC. Cell Signal 21:1672–1679

    Article  PubMed  CAS  Google Scholar 

  • Van Aelst L, Symons M (2002) Role of Rho family GTPases in epithelial morphogenesis. Genes Dev 16:1032–1054

    Article  PubMed  CAS  Google Scholar 

  • Vanhaesebroeck B et al (1997) P110delta, a novel phosphoinositide 3-kinase in leukocytes. Proc Natl Acad Sci USA 94:4330–4335

    Article  PubMed  CAS  Google Scholar 

  • Velho S et al (2005) The prevalence of PIK3CA mutations in gastric and colon cancer. Eur J Cancer 41:1649–1654

    Article  PubMed  CAS  Google Scholar 

  • Vivanco I, Sawyers CL (2002) The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2:489–501

    Article  PubMed  CAS  Google Scholar 

  • Voice JK et al (1999) Four human ras homologs differ in their abilities to activate Raf-1, induce transformation, and stimulate cell motility. J Biol Chem 274:17164–17170

    Article  PubMed  CAS  Google Scholar 

  • Vojtek AB et al (1993) Mammalian Ras interacts directly with the serine/threonine kinase Raf. Cell 74:205–214

    Article  PubMed  CAS  Google Scholar 

  • Walker EH et al (1999) Structural insights into phosphoinositide 3-kinase catalysis and signalling. Nature 402:313–320

    Article  PubMed  CAS  Google Scholar 

  • Walsh AB, Bar-Sagi D (2001) Differential activation of the Rac pathway by Ha-Ras and K-Ras. J Biol Chem 276:15609–15615

    Article  PubMed  CAS  Google Scholar 

  • Wang X et al (1998) The phosphorylation of eukaryotic initiation factor eIF4E in response to phorbol esters, cell stresses, and cytokines is mediated by distinct MAP kinase pathways. J Biol Chem 273:9373–9377

    Article  PubMed  CAS  Google Scholar 

  • Warne PH et al (1993) Direct interaction of Ras and the amino-terminal region of Raf-1 in vitro. Nature 364:352–355

    Article  PubMed  CAS  Google Scholar 

  • Waskiewicz AJ et al (1997) Mitogen-activated protein kinases activate the serine/threonine kinases Mnk1 and Mnk2. EMBO J 16:1909–1920

    Article  PubMed  CAS  Google Scholar 

  • Wee S et al (2009) PI3K pathway activation mediates resistance to MEK inhibitors in KRAS mutant cancers. Cancer Res 69:4286–4293

    Article  PubMed  CAS  Google Scholar 

  • Weiner OD et al (2002) A PtdInsP(3)- and Rho GTPase-mediated positive feedback loop regulates neutrophil polarity. Nat Cell Biol 4:509–513

    Article  PubMed  CAS  Google Scholar 

  • White MA et al (1996) A role for the Ral guanine nucleotide dissociation stimulator in mediating Ras-induced transformation. J Biol Chem 271:16439–16442

    Article  PubMed  CAS  Google Scholar 

  • Whiteford CC et al (1996) D-3 phosphoinositide metabolism in cells treated with platelet-derived growth factor. Biochem J 319(Pt 3):851–860

    PubMed  CAS  Google Scholar 

  • Wishart MJ, Dixon JE (2002) PTEN and myotubularin phosphatases: from 3-phosphoinositide dephosphorylation to disease. Trends Cell Biol 12:579–585

    Article  PubMed  CAS  Google Scholar 

  • Wittinghofer A, Nassar N (1996) How Ras-related proteins talk to their effectors. Trends Biochem Sci 21:488–491

    Article  PubMed  CAS  Google Scholar 

  • Wittinghofer A, Pai EF (1991) The structure of Ras protein: a model for a universal molecular switch. Trends Biochem Sci 16:382–387

    Article  PubMed  CAS  Google Scholar 

  • Wolfman A, Macara IG (1990) A cytosolic protein catalyzes the release of GDP from p21ras. Science 248:67–69

    Article  PubMed  CAS  Google Scholar 

  • Yamamoto H et al (2008) PIK3CA mutations and copy number gains in human lung cancers. Cancer Res 68:6913–6921

    Article  PubMed  CAS  Google Scholar 

  • Yan J et al (1998) Ras isoforms vary in their ability to activate Raf-1 and phosphoinositide 3-kinase. J Biol Chem 273:24052–24056

    Article  PubMed  CAS  Google Scholar 

  • Ye M et al (2008) Involvement of PI3K/Akt signaling pathway in hepatocyte growth factor-induced migration of uveal melanoma cells. Invest Ophthalmol Vis Sci 49:497–504

    Article  PubMed  Google Scholar 

  • Zhan M et al (2004) Signalling mechanisms of anoikis. Histol Histopathol 19:973–983

    PubMed  CAS  Google Scholar 

  • Zhang XF et al (1993) Normal and oncogenic p21ras proteins bind to the amino-terminal regulatory domain of c-Raf-1. Nature 364:308–313

    Article  PubMed  CAS  Google Scholar 

  • Zhang H et al (2007) PDGFRs are critical for PI3K/Akt activation and negatively regulated by mTOR. J Clin Invest 117:730–738

    Article  PubMed  CAS  Google Scholar 

  • Zhao L, Vogt PK (2008a) Class I PI3K in oncogenic cellular transformation. Oncogene 27:5486–5496

    Article  PubMed  CAS  Google Scholar 

  • Zhao L, Vogt PK (2008b) Helical domain and kinase domain mutations in p110alpha of phosphatidylinositol 3-kinase induce gain of function by different mechanisms. Proc Natl Acad Sci USA 105:2652–2657

    Article  PubMed  CAS  Google Scholar 

  • Zhao JJ et al (2005) The oncogenic properties of mutant p110alpha and p110beta phosphatidylinositol 3-kinases in human mammary epithelial cells. Proc Natl Acad Sci USA 102:18443–18448

    Article  PubMed  CAS  Google Scholar 

  • Zhao JJ et al (2006) The p110alpha isoform of PI3K is essential for proper growth factor signaling and oncogenic transformation. Proc Natl Acad Sci USA 103:16296–16300

    Article  PubMed  CAS  Google Scholar 

  • Zhu Y, Parada LF (2001) A particular GAP in mind. Nat Genet 27:354–355

    Article  PubMed  CAS  Google Scholar 

  • Zimmermann S, Moelling K (1999) Phosphorylation and regulation of Raf by Akt (protein kinase B). Science 286:1741–1744

    Article  PubMed  CAS  Google Scholar 

  • Zohn IM et al (1998) Rho family proteins and Ras transformation: the RHOad less traveled gets congested. Oncogene 17:1415–1438

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Signal Transduction Laboratory, Cancer Research UK London Research Institute, 44 Lincoln’s Inn Fields, London, WC2A 3PX, UK

    Esther Castellano & Julian Downward

Authors
  1. Esther Castellano
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Julian Downward
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Julian Downward .

Editor information

Editors and Affiliations

  1. Intellikine, North Torreye Pines Road 10931, La Jolla, 92037, California, USA

    Christian Rommel

  2. , Institute of Cancer and the London Schoo, Queen Mary, University of London, Charterhouse Square, London, EC1M 6BQ, United Kingdom

    Bart Vanhaesebroeck

  3. , Dept. Molecular & Exp. Medicine, Scripps Research Institute, N. Torrey Pines Road 10550, La Jolla, 92037, California, USA

    Peter K. Vogt

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Castellano, E., Downward, J. (2010). Role of RAS in the Regulation of PI 3-Kinase. In: Rommel, C., Vanhaesebroeck, B., Vogt, P. (eds) Phosphoinositide 3-kinase in Health and Disease. Current Topics in Microbiology and Immunology, vol 346. Springer, Berlin, Heidelberg. https://doi.org/10.1007/82_2010_56

Download citation

Publish with us

Policies and ethics

Search

Navigation