Crosstalk Between Mitogen-Activated Protein Kinase and Phosphoinositide-3 Kinase Signaling Pathways in Development and Disease

In animals, myriad chemical signals flow between and within cells to maintain life’s balancing act. The “flow” of these signals, or signaling pathways, ultimately dictates how cells respond to changes in their environment, from local tissue injury to food scarcity. During embryogenesis, the same signaling pathways function to transduce extracellular cues that guide development. Two of the most ubiquitous and evolutionarily conserved cell signaling pathways are the mitogen-activated protein kinase (MAPK) and the phosphoinositide-3 kinase (PI3K) pathways. The two pathways are involved in a wide range of critical cellular functions, such as cell growth and differentiation. They are also linked together as a part of a complex signaling network that regulates embryonic development, and the disruption of this network can result in a variety of diseases like cancers. Consequently, better mechanistic understanding of the MAPK and PI3K pathways and the crosstalk between them will inform strategies for future therapy. In this chapter, we will discuss the role of the MAPK and PI3K pathways in animal development and neoplastic transformations, with a focus on the role of multiple layers of crosstalk that go on between the two pathways.

[1]  R. Marais,et al.  14-3-3 Antagonizes Ras-Mediated Raf-1 Recruitment to the Plasma Membrane To Maintain Signaling Fidelity , 2002, Molecular and Cellular Biology.

[2]  M. Fishman,et al.  gridlock, an HLH gene required for assembly of the aorta in zebrafish. , 2000, Science.

[3]  Jeffrey A. Engelman,et al.  Targeting PI3K signalling in cancer: opportunities, challenges and limitations , 2009, Nature Reviews Cancer.

[4]  J. Hecht,et al.  Multicenter phase II study of the oral MEK inhibitor, CI-1040, in patients with advanced non-small-cell lung, breast, colon, and pancreatic cancer. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[5]  Hong Wu,et al.  Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[6]  C. Arteaga,et al.  Herceptin-induced inhibition of phosphatidylinositol-3 kinase and Akt Is required for antibody-mediated effects on p27, cyclin D1, and antitumor action. , 2002, Cancer research.

[7]  C. Sawyers,et al.  The phosphatidylinositol 3-Kinase–AKT pathway in human cancer , 2002, Nature Reviews Cancer.

[8]  E. Hafen,et al.  A Drosophila SH2-SH3 adaptor protein implicated in coupling the sevenless tyrosine kinase to an activator of Ras guanine nucleotide exchange, Sos , 1993, Cell.

[9]  S. Horvath,et al.  Antitumor Activity of Rapamycin in a Phase I Trial for Patients with Recurrent PTEN-Deficient Glioblastoma , 2008, PLoS medicine.

[10]  M. Janners,et al.  The initiation of limb bud outgrowth in the embryonic chick. , 1971, Developmental biology.

[11]  L. Cantley,et al.  ERK Negatively Regulates the Epidermal Growth Factor-mediated Interaction of Gab1 and the Phosphatidylinositol 3-Kinase* , 2002, The Journal of Biological Chemistry.

[12]  C. Niemeyer,et al.  RAS mutations and clonality analysis in children with juvenile myelomonocytic leukemia (JMML) , 1999, Leukemia.

[13]  J. Campos-Ortega,et al.  Notch signaling is required for arterial-venous differentiation during embryonic vascular development. , 2001, Development.

[14]  D. Brat,et al.  Tuberous sclerosis-associated neoplasms express activated p42/44 mitogen-activated protein (MAP) kinase, and inhibition of MAP kinase signaling results in decreased in vivo tumor growth. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[15]  D. Moore,et al.  Gemcitabine and ISIS-2503 for patients with locally advanced or metastatic pancreatic adenocarcinoma: a North Central Cancer Treatment Group phase II trial. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[16]  Michael Tsang,et al.  Promotion and Attenuation of FGF Signaling Through the Ras-MAPK Pathway , 2004, Science's STKE.

[17]  A. Moon.  Differential functions of ras for malignant phenotypic conversion , 2006, Archives of pharmacal research.

[18]  C. Der,et al.  Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer , 2007, Oncogene.

[19]  A. Ashworth,et al.  The Dual Specificity Phosphatases M3/6 and MKP-3 Are Highly Selective for Inactivation of Distinct Mitogen-activated Protein Kinases* , 1996, The Journal of Biological Chemistry.

[20]  D J Glass,et al.  Differentiation stage-specific inhibition of the Raf-MEK-ERK pathway by Akt. , 1999, Science.

[21]  Christopher U. Jones,et al.  Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. , 2006, The New England journal of medicine.

[22]  W. Kolch,et al.  Negative regulation of Raf-1 by phosphorylation of serine 621 , 1996, Molecular and cellular biology.

[23]  J. Massagué.  TGF-beta signal transduction. , 1998, Annual review of biochemistry.

[24]  Tobias Schmelzle,et al.  TOR, a Central Controller of Cell Growth , 2000, Cell.

[25]  G. Mills,et al.  Loss of PTEN/MMAC1/TEP in EGF receptor-expressing tumor cells counteracts the antitumor action of EGFR tyrosine kinase inhibitors , 2003, Oncogene.

[26]  G. Martin,et al.  The roles of FGFs in the early development of vertebrate limbs. , 1998, Genes & development.

[27]  T. Cloughesy,et al.  PTEN-Mediated Resistance to Epidermal Growth Factor Receptor Kinase Inhibitors , 2007, Clinical Cancer Research.

[28]  P. Dennis,et al.  Novel PI analogues selectively block activation of the pro-survival serine/threonine kinase Akt. , 2003, Journal of the American Chemical Society.

[29]  F. McCormick.  How receptors turn Ras on , 1993, Nature.

[30]  Y. Yarden,et al.  Untangling the ErbB signalling network , 2001, Nature Reviews Molecular Cell Biology.

[31]  K. Moelling,et al.  Regulation of Raf by Akt Controls Growth and Differentiation in Vascular Smooth Muscle Cells* , 2001, The Journal of Biological Chemistry.

[32]  Colin B. Reese,et al.  3-Phosphoinositide-dependent protein kinase-1 (PDK1): structural and functional homology with the Drosophila DSTPK61 kinase , 1997, Current Biology.

[33]  L. Presta,et al.  Humanization of an anti-p185HER2 antibody for human cancer therapy. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[34]  R. Peterson,et al.  Artery/Vein Specification Is Governed by Opposing Phosphatidylinositol-3 Kinase and MAP Kinase/ERK Signaling , 2006, Current Biology.

[35]  G. Rubin,et al.  An SH3-SH2-SH3 protein is required for p21 Ras1 activation and binds to sevenless and Sos proteins in vitro , 1993, Cell.

[36]  Lewis C Cantley,et al.  The phosphoinositide 3-kinase pathway. , 2002, Science.

[37]  H. Broxmeyer,et al.  Coupling between P210bcr-abl and Shc and Grb2 Adaptor Proteins in Hematopoietic Cells Pe~iiii~ Growth Factor Receptor-independent Link to Ras Activation Pathway , 1994 .

[38]  C. Marshall,et al.  Ras recruits Raf‐1 to the plasma membrane for activation by tyrosine phosphorylation. , 1995, The EMBO journal.

[39]  T. Fleming,et al.  Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. , 2001, The New England journal of medicine.

[40]  Nanxin Li,et al.  Guanine-nucleotide-releasing factor hSos1 binds to Grb2 and links receptor tyrosine kinases to Ras signalling , 1993, Nature.

[41]  R. Memmott,et al.  Handicapping the Race to Develop Inhibitors of the Phosphoinositide 3-Kinase/Akt/Mammalian Target of Rapamycin Pathway , 2006, Clinical Cancer Research.

[42]  Francisco Cervantes,et al.  Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. , 2003, The New England journal of medicine.

[43]  M. Dowsett,et al.  Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. , 2005, The New England journal of medicine.

[44]  A. Godwin,et al.  A Grb2-associated docking protein in EGF- and insulin-receptor signalling , 1996, Nature.

[45]  Yan Li,et al.  Regulation of Notch1 and Dll4 by Vascular Endothelial Growth Factor in Arterial Endothelial Cells: Implications for Modulating Arteriogenesis and Angiogenesis , 2003, Molecular and Cellular Biology.

[46]  E K Rowinsky,et al.  Ras protein farnesyltransferase: A strategic target for anticancer therapeutic development. , 1999, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[47]  A. Di Cristofano,et al.  Oncogenic Kras requires simultaneous PI3K signaling to induce ERK activation and transform thyroid epithelial cells in vivo. , 2009, Cancer research.

[48]  L. Cantley,et al.  New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[49]  P. Wipf,et al.  Molecular pharmacology and antitumor activity of PX-866, a novel inhibitor of phosphoinositide-3-kinase signaling. , 2004, Molecular cancer therapeutics.

[50]  I. Lax,et al.  The docking protein FRS2alpha controls a MAP kinase-mediated negative feedback mechanism for signaling by FGF receptors. , 2002, Molecular cell.

[51]  B. Weinstein,et al.  sonic hedgehog and vascular endothelial growth factor act upstream of the Notch pathway during arterial endothelial differentiation. , 2002, Developmental cell.

[52]  Jürg Zimmermann,et al.  Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr–Abl positive cells , 1996, Nature Medicine.

[53]  A. D. Van den Abbeele,et al.  Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[54]  J. Ptak,et al.  High Frequency of Mutations of the PIK3CA Gene in Human Cancers , 2004, Science.

[55]  J. Bos,et al.  B cell antigen receptor stimulation induces formation of a Shc-Grb2 complex containing multiple tyrosine-phosphorylated proteins. , 1994, The Journal of biological chemistry.

[56]  D. Donoghue,et al.  RTK mutations and human syndromeswhen good receptors turn bad. , 2000, Trends in genetics : TIG.

[57]  R. Snell,et al.  Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products. , 1998, Human molecular genetics.

[58]  W. Birchmeier,et al.  Interaction between Gab1 and the c-Met receptor tyrosine kinase is responsible for epithelial morphogenesis , 1996, Nature.

[59]  J. C. Belmonte,et al.  MKP3 mediates the cellular response to FGF8 signalling in the vertebrate limb , 2003, Nature Cell Biology.

[60]  J. McCubrey,et al.  Involvement of PI3K/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: a target for cancer chemotherapy , 2003, Leukemia.

[61]  C. Tickle,et al.  Negative Feedback Regulation of FGF Signaling Levels by Pyst1/MKP3 in Chick Embryos , 2003, Current Biology.

[62]  C. Tickle,et al.  Negative feedback predominates over cross‐regulation to control ERK MAPK activity in response to FGF signalling in embryos , 2006, FEBS letters.

[63]  Joseph Avruch,et al.  Rheb Binds and Regulates the mTOR Kinase , 2005, Current Biology.

[64]  Ralph Weissleder,et al.  Effective Use of PI3K and MEK Inhibitors to Treat Mutant K-Ras G12D and PIK3CA H1047R Murine Lung Cancers , 2008, Nature Medicine.

[65]  J. Camonis,et al.  A yeast two‐hybrid study of human p97/Gab2 interactions with its SH2 domain‐containing binding partners , 2001, FEBS letters.

[66]  H. Chap,et al.  Phosphoinositide 3-kinases in lysophosphatidic acid signaling: regulation and cross-talk with the Ras/mitogen-activated protein kinase pathway. , 2002, Biochimica et biophysica acta.

[67]  S. Sebti,et al.  Farnesyltransferase and geranylgeranyltransferase I inhibitors in cancer therapy: important mechanistic and bench to bedside issues , 2000, Expert opinion on investigational drugs.

[68]  Apurva A Desai,et al.  Sorafenib in advanced clear-cell renal-cell carcinoma. , 2007, The New England journal of medicine.

[69]  A. Eychène,et al.  sst2 Somatostatin Receptor Inhibits Cell Proliferation through Ras-, Rap1-, and B-Raf-dependent ERK2 Activation* , 2003, Journal of Biological Chemistry.

[70]  T. Kudoh,et al.  Identification of Sef, a novel modulator of FGF signalling , 2002, Nature Cell Biology.

[71]  T. Pawson,et al.  A novel transforming protein (SHC) with an SH2 domain is implicated in mitogenic signal transduction , 1992, Cell.

[72]  J. Boyd,et al.  Mutation analysis of the putative tumor suppressor gene PTEN/MMAC1 in primary breast carcinomas. , 1997, Cancer research.

[73]  E. Jabs,et al.  Clinical spectrum of fibroblast growth factor receptor mutations , 1999, Human mutation.

[74]  J. Baselga,et al.  Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[75]  W. Kolch,et al.  Cyclic AMP-Dependent Kinase Regulates Raf-1 Kinase Mainly by Phosphorylation of Serine 259 , 2002, Molecular and Cellular Biology.

[76]  A. Nicholson,et al.  Mutations of the BRAF gene in human cancer , 2002, Nature.

[77]  A. Ullrich,et al.  The SH2 and SH3 domain-containing protein GRB2 links receptor tyrosine kinases to ras signaling , 1992, Cell.

[78]  Fu-Jung Lin,et al.  Suppression of Notch signalling by the COUP-TFII transcription factor regulates vein identity , 2005, Nature.

[79]  J. W. Saunders.  The proximo-distal sequence of origin of the parts of the chick wing and the role of the ectoderm. 1948. , 1998, The Journal of experimental zoology.

[80]  P. Hordijk,et al.  Gi‐mediated activation of the Ras/MAP kinase pathway involves a 100 kDa tyrosine‐phosphorylated Grb2 SH3 binding protein, but not Src nor Shc , 1997, The EMBO journal.

[81]  K. Inoki,et al.  TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling , 2002, Nature Cell Biology.

[82]  M. Muda,et al.  MKP-3, a Novel Cytosolic Protein-tyrosine Phosphatase That Exemplifies a New Class of Mitogen-activated Protein Kinase Phosphatase (*) , 1996, The Journal of Biological Chemistry.

[83]  V. P. Eswarakumar,et al.  Cellular signaling by fibroblast growth factor receptors. , 2005, Cytokine & growth factor reviews.

[84]  G. Martin,et al.  Functions of FGF signalling from the apical ectodermal ridge in limb development , 2002, Nature.

[85]  Armando Santoro,et al.  Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. , 2004, The New England journal of medicine.

[86]  P. Leder,et al.  Fibroblast growth factor receptor 2 (FGFR2)-mediated reciprocal regulation loop between FGF8 and FGF10 is essential for limb induction. , 1998, Development.

[87]  K. Moelling,et al.  Phosphorylation and regulation of Raf by Akt (protein kinase B). , 1999, Science.

[88]  B. Monia,et al.  Antisense Oligonucleotides Demonstrate a Dominant Role of c-Ki-RAS Proteins in Regulating the Proliferation of Diploid Human Fibroblasts* , 1996, The Journal of Biological Chemistry.

[89]  Todd R. Golub,et al.  BRAF mutation predicts sensitivity to MEK inhibition , 2006, Nature.

[90]  J. McCubrey,et al.  Signal transduction mediated by the Ras/Raf/MEK/ERK pathway from cytokine receptors to transcription factors: potential targeting for therapeutic intervention , 2003, Leukemia.

[91]  L. Cantley,et al.  Differential MAPK Pathways Utilized for HGF- and EGF-dependent Renal Epithelial Morphogenesis* , 2001, The Journal of Biological Chemistry.

[92]  G. Thomas,et al.  TOR signalling and control of cell growth. , 1997, Current opinion in cell biology.

[93]  Michael J. Fry,et al.  Phosphatidylinositol-3-OH kinase direct target of Ras , 1994, Nature.

[94]  K. Guan,et al.  Positive and negative regulation of Raf kinase activity and function by phosphorylation , 2001, The EMBO journal.

[95]  Keith T Flaherty,et al.  Multiple signaling pathways must be targeted to overcome drug resistance in cell lines derived from melanoma metastases , 2006, Molecular Cancer Therapeutics.

[96]  Joseph Schlessinger,et al.  Signal transduction by receptors with tyrosine kinase activity , 1990, Cell.

[97]  A. Oliff,et al.  Farnesyltransferase inhibitors: targeting the molecular basis of cancer. , 1999, Biochimica et biophysica acta.

[98]  P. Crespo,et al.  Linkage of G Protein-Coupled Receptors to the MAPK Signaling Pathway Through PI 3-Kinase γ , 1997, Science.

[99]  T. Kuwana,et al.  The mesenchymal factor, FGF10, initiates and maintains the outgrowth of the chick limb bud through interaction with FGF8, an apical ectodermal factor. , 1997, Development.

[100]  M. Cobb,et al.  Identification of multiple extracellular signal-regulated kinases (ERKs) with antipeptide antibodies. , 1991, Cell regulation.

[101]  J. Radich,et al.  FLT3, RAS, and TP53 mutations in elderly patients with acute myeloid leukemia. , 2001, Blood.

[102]  K. Kolibaba,et al.  Protein tyrosine kinases and cancer. , 1997, Biochimica et biophysica acta.

[103]  G. Bollag,et al.  Discovery of a novel Raf kinase inhibitor. , 2001, Endocrine-related cancer.

[104]  M. Globus,et al.  An in vitro analogue of early chick limb bud outgrowth. , 1976, Differentiation; research in biological diversity.

[105]  M. Fürthauer,et al.  Sef is a feedback-induced antagonist of Ras/MAPK-mediated FGF signalling , 2002, Nature Cell Biology.

[106]  C. Crews,et al.  Extracellular signals and reversible protein phosphorylation: What to Mek of it all , 1993, Cell.

[107]  Paul Tempst,et al.  Phosphorylation and Functional Inactivation of TSC2 by Erk Implications for Tuberous Sclerosisand Cancer Pathogenesis , 2005, Cell.

[108]  Tony Pawson,et al.  Protein modules and signalling networks , 1995, Nature.

[109]  T Pawson,et al.  Formation of Shc-Grb2 complexes is necessary to induce neoplastic transformation by overexpression of Shc proteins. , 1994, Oncogene.

[110]  Túlio Marcos Santos,et al.  Phosphorylation of Tuberin as a Novel Mechanism for Somatic Inactivation of the Tuberous Sclerosis Complex Proteins in Brain Lesions , 2004, Cancer Research.

[111]  T. Kume,et al.  Foxc Transcription Factors Directly Regulate Dll4 and Hey2 Expression by Interacting with the VEGF-Notch Signaling Pathways in Endothelial Cells , 2008, PloS one.

[112]  Alexander F Schier,et al.  Molecular genetics of axis formation in zebrafish. , 2005, Annual review of genetics.

[113]  M. Cobb,et al.  Extracellular signal-regulated kinases: ERKs in progress. , 1991, Cell regulation.

[114]  Phillip T. Hawkins,et al.  Crystal Structure and Functional Analysis of Ras Binding to Its Effector Phosphoinositide 3-Kinase γ , 2000, Cell.

[115]  R. Weinberg,et al.  Human EJ bladder carcinoma oncogene is homologue of Harvey sarcoma virus ras gene , 1982, Nature.

[116]  L. Cantley,et al.  Ras, PI(3)K and mTOR signalling controls tumour cell growth , 2006, Nature.

[117]  T. Pawson,et al.  Overexpression of Shc proteins potentiates the proliferative response to the granulocyte-macrophage colony-stimulating factor and recruitment of Grb2/SoS and Grb2/p140 complexes to the beta receptor subunit. , 1995, Oncogene.

[118]  Steven P Gygi,et al.  Quantitative phosphorylation profiling of the ERK/p90 ribosomal S6 kinase-signaling cassette and its targets, the tuberous sclerosis tumor suppressors. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[119]  C. Crews,et al.  The primary structure of MEK, a protein kinase that phosphorylates the ERK gene product. , 1992, Science.

[120]  J. Baselga,et al.  Targeting Tyrosine Kinases in Cancer: The Second Wave , 2006, Science.

[121]  A. Ullrich,et al.  Receptor tyrosine kinase signalling as a target for cancer intervention strategies. , 2001, Endocrine-related cancer.

[122]  M. Shibuya,et al.  A single autophosphorylation site on KDR/Flk‐1 is essential for VEGF‐A‐dependent activation of PLC‐γ and DNA synthesis in vascular endothelial cells , 2001, The EMBO journal.

[123]  H. Ohuchi,et al.  FGF7 and FGF10 directly induce the apical ectodermal ridge in chick embryos. , 1999, Developmental biology.

[124]  Koji Yoshimoto,et al.  Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. , 2005, The New England journal of medicine.

[125]  M. Barbacid,et al.  T24 human bladder carcinoma oncogene is an activated form of the normal human homologue of BALB- and Harvey-MSV transforming genes , 1982, Nature.

[126]  J. Blenis,et al.  Signal transduction via the MAP kinases: proceed at your own RSK. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[127]  B. Weinstein,et al.  phospholipase C gamma-1 is required downstream of vascular endothelial growth factor during arterial development. , 2003, Genes & development.

[128]  D. von der Ahe,et al.  An Inhibitory Role of the Phosphatidylinositol 3-Kinase-signaling Pathway in Vascular Endothelial Growth Factor-induced Tissue Factor Expression* , 2001, The Journal of Biological Chemistry.

[129]  R S Reiter,et al.  Mitogenic property of the apical ectodermal ridge. , 1982, Developmental biology.

[130]  P. Seeburg,et al.  Human epidermal growth factor receptor cDNA sequence and aberrant expression of the amplified gene in A431 epidermoid carcinoma cells , 1984, Nature.

[131]  J. Downward,et al.  Role of Phosphoinositide 3-Kinase in Activation of Ras and Mitogen-Activated Protein Kinase by Epidermal Growth Factor , 1999, Molecular and Cellular Biology.

[132]  Ji Luo,et al.  The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism , 2006, Nature Reviews Genetics.

[133]  M. Shibuya,et al.  VEGF activates protein kinase C-dependent, but Ras-independent Raf-MEK-MAP kinase pathway for DNA synthesis in primary endothelial cells , 1999, Oncogene.

[134]  G. Christofori.  Split personalities: the agonistic antagonist Sprouty , 2003, Nature Cell Biology.

[135]  A. Ashworth,et al.  Identification of the sites in MAP kinase kinase‐1 phosphorylated by p74raf‐1. , 1994, The EMBO journal.

[136]  P. Krieg,et al.  VEGF mediates angioblast migration during development of the dorsal aorta in Xenopus. , 1998, Development.

[137]  K. Fransén,et al.  Mutation analysis of the BRAF, ARAF and RAF-1 genes in human colorectal adenocarcinomas. , 2003, Carcinogenesis.

[138]  Lyndsay N Harris,et al.  Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.