Regulation of cell size in growth, development and human disease: PI3K, PKB and S6K

It has generally been observed that cells grow to a certain size before they divide. In the last few years, the PI3K signal transduction pathway has emerged as one of the main signaling routes utilized by cells to control their increase in size. Here we focus on two components of this pathway, PKB and S6K, and briefly review the experiments that initially uncovered their roles in cell size control. In addition, we discuss a number of recent observations suggesting that the generic models used to describe this pathway to date may have been oversimplified. Indeed, recent observations in Drosophila and mouse support a more complex interaction between these signaling components in development. Finally, we have utilized two contemporary studies involving PKB‐ and S6K‐deficient mice as a paradigm to underscore the importance of cell size and to accurately delineate the connections between signaling pathways for human disease, such as diabetes mellitus. BioEssays 24:65–71, 2002. © 2002 John Wiley & Sons, Inc.

[1]  T. Hunter,et al.  Oncogenic kinase signalling , 2001, Nature.

[2]  B. Hemmings Update: PtdIns(3,4,5)P3 Gets Its Message Across , 1997, Science.

[3]  K. Khanna,et al.  DNA double-strand breaks: signaling, repair and the cancer connection , 2001, Nature Genetics.

[4]  P. Berggren,et al.  Exocytosis of insulin promotes insulin gene transcription via the insulin receptor/PI-3 kinase/p70 s6 kinase and CaM kinase pathways. , 1998, Molecular cell.

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

[6]  I. Conlon,et al.  Size Control in Animal Development , 1999, Cell.

[7]  B. Kahn Type 2 Diabetes: When Insulin Secretion Fails to Compensate for Insulin Resistance , 1998, Cell.

[8]  E. Hafen,et al.  Drosophila S6 kinase: a regulator of cell size. , 1999, Science.

[9]  D. Goberdhan,et al.  Drosophila tumor suppressor PTEN controls cell size and number by antagonizing the Chico/PI3-kinase signaling pathway. , 1999, Genes & development.

[10]  L. Borg,et al.  Persistent reduction of pancreatic Beta-cell mass after a limited period of protein-energy malnutrition in the young rat , 1992, Diabetologia.

[11]  G. Thomas An encore for ribosome biogenesis in the control of cell proliferation , 2000, Nature Cell Biology.

[12]  M. White,et al.  Insulin-like growth factor I (IGF-I)-stimulated pancreatic beta-cell growth is glucose-dependent. Synergistic activation of insulin receptor substrate-mediated signal transduction pathways by glucose and IGF-I in INS-1 cells. , 1998, The Journal of biological chemistry.

[13]  C. Lehner,et al.  Cell cycle progression, growth and patterning in imaginal discs despite inhibition of cell division after inactivation of Drosophila Cdc2 kinase. , 1997, Development.

[14]  J. Downward Lipid-Regulated Kinases: Some Common Themes at Last , 1998, Science.

[15]  Paul Nurse,et al.  Genetic control of cell size at cell division in yeast , 1975, Nature.

[16]  N. Sonenberg,et al.  The translational inhibitor 4E-BP is an effector of PI(3)K/Akt signalling and cell growth in Drosophila , 2001, Nature Cell Biology.

[17]  Peer Bork,et al.  HEAT repeats in the Huntington's disease protein , 1995, Nature Genetics.

[18]  J. Blenis,et al.  Structural and functional analysis of pp70S6k. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[19]  E. Hafen,et al.  PTEN affects cell size, cell proliferation and apoptosis during Drosophila eye development. , 1999, Development.

[20]  C. Potter,et al.  Drosophila Tsc1 Functions with Tsc2 to Antagonize Insulin Signaling in Regulating Cell Growth, Cell Proliferation, and Organ Size , 2001, Cell.

[21]  M. Andjelkovic,et al.  Phosphorylation and activation of p70s6k by PDK1. , 1998, Science.

[22]  E. Hafen,et al.  Genetic control of cell size. , 2000, Current opinion in genetics & development.

[23]  I. Swenne,et al.  Intermittent protein-calorie malnutrition in the young rat causes long-term impairment of the insulin secretory response to glucose in vitro. , 1988, The Journal of endocrinology.

[24]  B. Dickson,et al.  The Drosophila Tuberous Sclerosis Complex Gene Homologs Restrict Cell Growth and Cell Proliferation , 2001, Cell.

[25]  P. Cohen,et al.  Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B , 1995, Nature.

[26]  G. Sesti,et al.  Insulin receptor substrate (IRS) transduction system: distinct and overlapping signaling potential , 2000, Diabetes/metabolism research and reviews.

[27]  B. Edgar From small flies come big discoveries about size control , 1999, Nature Cell Biology.

[28]  C. Kahn,et al.  Alternative pathway of insulin signalling in mice with targeted disruption of the IRS-1 gene , 1994, Nature.

[29]  H. Onda,et al.  Tuberous Sclerosis Gene 2 Product Modulates Transcription Mediated by Steroid Hormone Receptor Family Members* , 1998, The Journal of Biological Chemistry.

[30]  M. Wigler,et al.  P-TEN, the tumor suppressor from human chromosome 10q23, is a dual-specificity phosphatase. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[31]  E. Hafen,et al.  Genetic and biochemical characterization of dTOR, the Drosophila homolog of the target of rapamycin. , 2000, Genes & development.

[32]  Dario R. Alessi,et al.  3-Phosphoinositide-dependent protein kinase 1 (PDK1) phosphorylates and activates the p70 S6 kinase in vivo and in vitro , 1998, Current Biology.

[33]  I. Swenne,et al.  Pancreatic Beta-cell growth and diabetes mellitus , 1992, Diabetologia.

[34]  K. Kaestner,et al.  Insulin Resistance and a Diabetes Mellitus-Like Syndrome in Mice Lacking the Protein Kinase Akt2 (PKBβ) , 2001 .

[35]  Brian A. Hemmings,et al.  Protein Kinase B Localization and Activation Differentially Affect S6 Kinase 1 Activity and Eukaryotic Translation Initiation Factor 4E-Binding Protein 1 Phosphorylation , 1999, Molecular and Cellular Biology.

[36]  E. Golemis,et al.  The Tuberous Sclerosis 2 Gene Product, Tuberin, Functions as a Rab5 GTPase Activating Protein (GAP) in Modulating Endocytosis* , 1997, The Journal of Biological Chemistry.

[37]  G. Shulman,et al.  Disruption of IRS-2 causes type 2 diabetes in mice , 1998, Nature.

[38]  J. Slack Developmental biology of the pancreas. , 1995, Development.

[39]  C. Kahn,et al.  Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction. , 2000, Molecular cell.

[40]  J. Avruch,et al.  Molecular structure of a major insulin/mitogen-activated 70-kDa S6 protein kinase. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[41]  S Povey,et al.  The genetic basis of tuberous sclerosis. , 1998, Molecular medicine today.

[42]  Paul Tempst,et al.  RAFT1: A mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs , 1994, Cell.

[43]  Tin Tin Su,et al.  Size control: Cell proliferation does not equal growth , 1998, Current Biology.

[44]  Geert J. P. L. Kops,et al.  Direct control of the Forkhead transcription factor AFX by protein kinase B , 1999, Nature.

[45]  G. Thomas,et al.  Ribosomal S6 kinase signaling and the control of translation. , 1999, Experimental cell research.

[46]  R. Burcelin,et al.  Hypoinsulinaemia, glucose intolerance and diminished β-cell size in S6K1-deficient mice , 2000, Nature.

[47]  F. McCormick,et al.  Dual role of phosphatidylinositol-3,4,5-trisphosphate in the activation of protein kinase B. , 1997, Science.

[48]  A. Zetterberg,et al.  A quantitative cytochemical investigation of the relationship between cell mass and initiation of DNA synthesis in mouse fibroblasts in vitro. , 1965, Experimental cell research.

[49]  S. Snyder,et al.  RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[50]  S Povey,et al.  Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. , 1997, Science.

[51]  T. P. Neufeld,et al.  Regulation of cellular growth by the Drosophila target of rapamycin dTOR. , 2000, Genes & development.

[52]  Christine C. Hudson,et al.  Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin. , 1997, Science.

[53]  E. Hafen,et al.  Autonomous Control of Cell and Organ Size by CHICO, a Drosophila Homolog of Vertebrate IRS1–4 , 1999, Cell.

[54]  M. Siegmann,et al.  Cloning of the mitogen-activated S6 kinase from rat liver reveals an enzyme of the second messenger subfamily. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[55]  R. Iyengar,et al.  Signaling Networks The Origins of Cellular Multitasking , 2000, Cell.

[56]  Stuart L. Schreiber,et al.  A mammalian protein targeted by G1-arresting rapamycin–receptor complex , 1994, Nature.

[57]  P. Cohen,et al.  Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Bα , 1997, Current Biology.

[58]  L. Mayo,et al.  A phosphatidylinositol 3-kinase/Akt/mTOR pathway mediates and PTEN antagonizes tumor necrosis factor inhibition of insulin signaling through insulin receptor substrate-1 , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[59]  G C Johnston,et al.  Coordination of growth with cell division in the yeast Saccharomyces cerevisiae. , 1977, Experimental cell research.

[60]  C. Lehner The beauty of small flies , 1999, Nature Cell Biology.

[61]  Andrius Kazlauskas,et al.  PDGF- and insulin-dependent pp70S6k activation mediated by phosphatidylinositol-3-OH kinase , 1994, Nature.

[62]  Michael N. Hall,et al.  The TOR signalling pathway controls nuclear localization of nutrient-regulated transcription factors , 1999, Nature.

[63]  A. Gingras,et al.  Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5'-cap function , 1994, Nature.

[64]  J. Avruch,et al.  Multiple independent inputs are required for activation of the p70 S6 kinase , 1995, Molecular and cellular biology.

[65]  R. DeFronzo PATHOGENESIS OF TYPE 2 DIABETES: METABOLIC AND MOLECULAR IMPLICATIONS FOR IDENTIFYING DIABETES GENES , 1997 .

[66]  S. Leevers,et al.  Do growth and cell division rates determine cell size in multicellular organisms? , 2000, Journal of cell science.

[67]  A. Gingras,et al.  4E-BP1 phosphorylation is mediated by the FRAP-p70s6k pathway and is independent of mitogen-activated protein kinase. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[68]  E. Hafen,et al.  The Drosophila phosphoinositide 3‐kinase Dp110 promotes cell growth. , 1996, The EMBO journal.

[69]  A. Gingras,et al.  The insulin-induced signalling pathway leading to S6 and initiation factor 4E binding protein 1 phosphorylation bifurcates at a rapamycin-sensitive point immediately upstream of p70s6k , 1997, Molecular and cellular biology.

[70]  D. Phillips,et al.  Insulin resistance as a programmed response to fetal undernutrition , 1996, Diabetologia.

[71]  Xinsheng Gao,et al.  TSC1 and TSC2 tumor suppressors antagonize insulin signaling in cell growth. , 2001, Genes & development.

[72]  T. P. Neufeld,et al.  Coordination of Growth and Cell Division in the Drosophila Wing , 1998, Cell.

[73]  G. Thomas,et al.  Target of rapamycin (TOR): balancing the opposing forces of protein synthesis and degradation. , 1999, Current opinion in genetics & development.

[74]  Stefano Fumagalli,et al.  Disruption of the p70s6k/p85s6k gene reveals a small mouse phenotype and a new functional S6 kinase , 1998, The EMBO journal.

[75]  K. Esser,et al.  Transcriptional regulation in response to exercise. , 1999, Exercise and sport sciences reviews.

[76]  A. Gingras,et al.  Regulation of translation initiation by FRAP/mTOR. , 2001, Genes & development.

[77]  M. Waterfield,et al.  Signaling by distinct classes of phosphoinositide 3-kinases. , 1999, Experimental cell research.