Insulin-like growth factors (IGFs), IGF receptors, and IGF-binding proteins: roles in skeletal muscle growth and differentiation.

The insulin-like growth factor (IGF) signaling pathway consists of multiple IGF ligands, IGF receptors, and IGF-binding proteins (IGFBPs). Studies in a variety of animal and cellular systems suggest that the IGF signaling pathway plays a key role in regulating skeletal muscle growth, differentiation, and in maintaining homeostasis of the adult muscle tissues. Intriguingly, IGFs stimulate both myoblast proliferation and differentiation, which are two mutually exclusive biological events during myogenesis. Both of these actions are mediated through the same IGF-1 receptor. Recent studies have shed new insights into the molecular mechanisms underlying these paradoxical actions of IGFs in muscle cells. In this article, we provide a brief review of our current understanding of the IGF signaling system and discuss recent findings on how local oxygen availability and IGFBPs act to specify IGF actions in muscle cells.

[1]  S. Mohan,et al.  Modulation of insulin‐like growth factor actions in L6A1 myoblasts by insulin‐like growth factor binding protein (IGFBP)‐4 and IGFBP‐5: A dual role for IGFBP‐5 , 1998, Journal of cellular physiology.

[2]  R. Taub,et al.  Impaired Hepatocyte DNA Synthetic Response Posthepatectomy in Insulin-Like Growth Factor Binding Protein 1-Deficient Mice with Defects in C/EBPβ and Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Regulation , 2003, Molecular and Cellular Biology.

[3]  E. Wilson,et al.  Insulin-like growth factor (IGF) binding protein-5 blocks skeletal muscle differentiation by inhibiting IGF actions. , 2008, Molecular endocrinology.

[4]  A. Reeve,et al.  Insulin-like growth factor 2 and overgrowth: molecular biology and clinical implications. , 1998, Molecular medicine today.

[5]  S. Kajimura,et al.  Understanding Hypoxia-Induced Gene Expression in Early Development: In Vitro and In Vivo Analysis of Hypoxia-Inducible Factor 1-Regulated Zebra Fish Insulin-Like Growth Factor Binding Protein 1 Gene Expression , 2006, Molecular and Cellular Biology.

[6]  D. Pette.  The adaptive potential of skeletal muscle fibers. , 2002, Canadian journal of applied physiology = Revue canadienne de physiologie appliquee.

[7]  M. Rudnicki,et al.  Niche regulation of muscle satellite cell self-renewal and differentiation. , 2008, Cell stem cell.

[8]  C. Chen,et al.  Molecular and functional characterization of two distinct IGF binding protein-6 genes in zebrafish. , 2009, American journal of physiology. Regulatory, integrative and comparative physiology.

[9]  M. Blüher,et al.  Autocrine IGF-1 Action in Adipocytes Controls Systemic IGF-1 Concentrations and Growth , 2008, Diabetes.

[10]  A. Lassar,et al.  Wiring diagrams: regulatory circuits and the control of skeletal myogenesis. , 1994, Current opinion in cell biology.

[11]  D. Leroith,et al.  Insulin and Insulin-Like Growth Factor I Receptors: Similarities and Differences in Signal Transduction , 2004, Hormone Research in Paediatrics.

[12]  A. Giaccia,et al.  Hypoxic gene expression and metastasis , 2004, Cancer and Metastasis Reviews.

[13]  H. Bern,et al.  Insulin-like growth factor signaling in fish. , 2005, International review of cytology.

[14]  Stuart M Phillips.  Resistance exercise: good for more than just Grandma and Grandpa's muscles. , 2007, Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme.

[15]  N. Rosenthal,et al.  Proliferation precedes differentiation in IGF-I-stimulated myogenesis , 1996, The Journal of cell biology.

[16]  Robert J. Schwartz,et al.  Myogenic Vector Expression of Insulin-like Growth Factor I Stimulates Muscle Cell Differentiation and Myofiber Hypertrophy in Transgenic Mice (*) , 1995, The Journal of Biological Chemistry.

[17]  M. Bouxsein,et al.  Gender-specific changes in bone turnover and skeletal architecture in igfbp-2-null mice. , 2008, Endocrinology.

[18]  T. Maures,et al.  Structure, developmental expression, and physiological regulation of zebrafish IGF binding protein-1. , 2002, Endocrinology.

[19]  P. J. Schlueter,et al.  Targeted knockdown of insulin-like growth factor binding protein-2 disrupts cardiovascular development in zebrafish embryos. , 2005, Molecular endocrinology.

[20]  M. Baldwin,et al.  Expression, purification and characterization of the structure and disulfide linkages of insulin-like growth factor binding protein-4. , 2001, The Journal of endocrinology.

[21]  M. Stoffel,et al.  beta-cell-specific deletion of the Igf1 receptor leads to hyperinsulinemia and glucose intolerance but does not alter beta-cell mass. , 2002, Nature genetics.

[22]  T. Wood,et al.  Distinct expression patterns of insulin-like growth factor binding proteins 2 and 5 during fetal and postnatal development. , 1994, Endocrinology.

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

[24]  J. Florini,et al.  IGFs and muscle differentiation. , 1993, Advances in experimental medicine and biology.

[25]  J. O’Kusky,et al.  Mutant mouse models of insulin-like growth factor actions in the central nervous system , 2002, Neuropeptides.

[26]  W. Wright.  Muscle basic helix-loop-helix proteins and the regulation of myogenesis. , 1992, Current opinion in genetics & development.

[27]  G. Semenza,et al.  HIF-1 and human disease: one highly involved factor. , 2000, Genes & development.

[28]  M. White.  Insulin Signaling in Health and Disease , 2003, Science.

[29]  R. Baxter,et al.  Cellular actions of the insulin-like growth factor binding proteins. , 2002, Endocrine reviews.

[30]  J. Baker,et al.  Effects of an Igf1 gene null mutation on mouse reproduction. , 1996, Molecular endocrinology.

[31]  R. Taub,et al.  Massive hepatic apoptosis associated with TGF-beta1 activation after Fas ligand treatment of IGF binding protein-1-deficient mice. , 2003, The Journal of clinical investigation.

[32]  A. Maiorana,et al.  Late effects of disturbed IGF signaling in congenital diseases. , 2007, Endocrine development.

[33]  C. Holding,et al.  Insulin-like growth factor-binding protein 5 (Igfbp5) compromises survival, growth, muscle development, and fertility in mice , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[34]  C. Roberts,et al.  The insulin-like growth factor system and cancer. , 2003, Cancer letters.

[35]  P. White,et al.  Intranuclear localization of insulin-like growth factor binding protein-3 (IGFBP-3) during cell division in human keratinocytes. , 1998, The Journal of investigative dermatology.

[36]  R. Baxter,et al.  Insulin-like Growth Factor-binding Protein (IGFBP)-3 and IGFBP-5 Share a Common Nuclear Transport Pathway in T47D Human Breast Carcinoma Cells* , 1998, The Journal of Biological Chemistry.

[37]  R. Waterland,et al.  Tissue-specific inactivation of murine M6P/IGF2R. , 2003, The American journal of pathology.

[38]  F. Tronche,et al.  Hepatocyte proliferation during liver regeneration is impaired in mice with liver‐specific IGF‐1R knockout , 2006, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[39]  Ziying Liu,et al.  Loss of the imprinted IGF2/cation-independent mannose 6-phosphate receptor results in fetal overgrowth and perinatal lethality. , 1994, Genes & development.

[40]  E. Ayuso,et al.  Beta cell expression of IGF-I leads to recovery from type 1 diabetes. , 2002, The Journal of clinical investigation.

[41]  D. Feldman,et al.  Unraveling insulin-like growth factor binding protein-3 actions in human disease. , 2009, Endocrine reviews.

[42]  D. Clemmons,et al.  Differential Expression and Biological Effects of Insulin-like Growth Factor-binding Protein-4 and -5 in Vascular Smooth Muscle Cells* , 1998, The Journal of Biological Chemistry.

[43]  R. Rabkin,et al.  Nuclear transport of insulin-like growth factor-I and insulin-like growth factor binding protein-3 in opossum kidney cells. , 1997, Endocrinology.

[44]  E. Wilson,et al.  Selective Control of Skeletal Muscle Differentiation by Akt1* , 2007, Journal of Biological Chemistry.

[45]  T. Holak,et al.  The interaction of insulin‐like growth factor‐I with the N‐terminal domain of IGFBP‐5 , 2001, The EMBO journal.

[46]  S. Kajimura,et al.  Insulin-like growth factor-binding protein-1 (IGFBP-1) mediates hypoxia-induced embryonic growth and developmental retardation. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[47]  J R Florini,et al.  "Spontaneous" differentiation of skeletal myoblasts is dependent upon autocrine secretion of insulin-like growth factor-II. , 1991, The Journal of biological chemistry.

[48]  C. Holding,et al.  Partitioning of IGFBP-5 actions in myogenesis: IGF-independent anti-apoptotic function , 2004, Journal of Cell Science.

[49]  Z. Du,et al.  Duplicated zebrafish insulin‐like growth factor binding protein‐5 genes with split functional domains: evidence for evolutionarily conserved IGF binding, nuclear localization, and transactivation activity , 2010, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[50]  J. Wallace,et al.  Localization of an Insulin-like Growth Factor (IGF) Binding Site of Bovine IGF Binding Protein-2 Using Disulfide Mapping and Deletion Mutation Analysis of the C-terminal Domain* , 1998, The Journal of Biological Chemistry.

[51]  E. Froesch,et al.  Short-term metabolic effects of recombinant human insulin-like growth factor I in healthy adults. , 1987, The New England journal of medicine.

[52]  P. Yin,et al.  IGFBP-5 regulates muscle cell differentiation by binding to IGF-II and switching on the IGF-II auto-regulation loop , 2008, The Journal of cell biology.

[53]  M. Lawlor,et al.  Insulin-Like Growth Factor-Mediated Muscle Cell Survival: Central Roles for Akt and Cyclin-Dependent Kinase Inhibitor p21 , 2000, Molecular and Cellular Biology.

[54]  R. Palmiter,et al.  Growth enhancement of transgenic mice expressing human insulin-like growth factor I. , 1988, Endocrinology.

[55]  Antonio Musarò,et al.  Localized Igf-1 transgene expression sustains hypertrophy and regeneration in senescent skeletal muscle , 2001, Nature Genetics.

[56]  J. Eisen,et al.  Zebrafish Make a Big Splash , 1996, Cell.

[57]  M. Lawlor,et al.  Coordinate Control of Muscle Cell Survival by Distinct Insulin-like Growth Factor Activated Signaling Pathways , 2000, The Journal of cell biology.

[58]  C. Rommel,et al.  Mediation of IGF-1-induced skeletal myotube hypertrophy by PI(3)K/Akt/mTOR and PI(3)K/Akt/GSK3 pathways , 2001, Nature Cell Biology.

[59]  G. Bernardi,et al.  Stem cell-mediated muscle regeneration is enhanced by local isoform of insulin-like growth factor 1. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[60]  S. Xuan,et al.  Insulin-Like Growth Factor (IGF) Signaling through Type 1 IGF Receptor Plays an Important Role in Remyelination , 2003, The Journal of Neuroscience.

[61]  M. Koutsilieris,et al.  Type I insulin-like growth factor receptor signaling in skeletal muscle regeneration and hypertrophy. , 2007, Journal of musculoskeletal & neuronal interactions.

[62]  M. Palacín,et al.  Phosphatidylinositol 3-Kinase Inhibitors Block Differentiation of Skeletal Muscle Cells* , 1996, The Journal of Biological Chemistry.

[63]  D. Clemmons,et al.  Insulin-like growth factors and their binding proteins: biological actions. , 1995, Endocrine reviews.

[64]  C. Thompson,et al.  HIF and c-Myc: sibling rivals for control of cancer cell metabolism and proliferation. , 2007, Cancer cell.

[65]  T. Ludwig,et al.  Diminished growth and enhanced glucose metabolism in triple knockout mice containing mutations of insulin-like growth factor binding protein-3, -4, and -5. , 2006, Molecular endocrinology.

[66]  S. Zou,et al.  Zebrafish IGF Genes: Gene Duplication, Conservation and Divergence, and Novel Roles in Midline and Notochord Development , 2009, PloS one.

[67]  M. Westerfield,et al.  Insulin-like growth factor signaling regulates zebrafish embryonic growth and development by promoting cell survival and cell cycle progression , 2007, Cell Death and Differentiation.

[68]  J R Florini,et al.  Growth hormone and the insulin-like growth factor system in myogenesis. , 1996, Endocrine reviews.

[69]  Elizabeth J. Robertson,et al.  Role of insulin-like growth factors in embryonic and postnatal growth , 1993, Cell.

[70]  C. Conover,et al.  Insulin-like growth factor (IGF) binding protein-4 is both a positive and negative regulator of IGF activity in vivo. , 2008, Molecular endocrinology.

[71]  R. Baxter,et al.  Nuclear Import of Insulin-like Growth Factor-binding Protein-3 and -5 Is Mediated by the Importin β Subunit* , 2000, The Journal of Biological Chemistry.

[72]  L. Wold,et al.  IGF-I attenuates diabetes-induced cardiac contractile dysfunction in ventricular myocytes. , 2002, American journal of physiology. Endocrinology and metabolism.

[73]  E. Olson.  MyoD family: a paradigm for development? , 1990, Genes & development.

[74]  J. Silha,et al.  Minireview: Insights from Insulin-Like Growth Factor Binding Protein Transgenic Mice , 2002 .

[75]  L. Powell-Braxton,et al.  IGF-I is required for normal embryonic growth in mice. , 1993, Genes & development.

[76]  C. Oxvig,et al.  Duplication and Diversification of the Hypoxia-Inducible IGFBP-1 Gene in Zebrafish , 2008, PloS one.

[77]  E. Wilson,et al.  Permissive roles of phosphatidyl inositol 3-kinase and Akt in skeletal myocyte maturation. , 2003, Molecular biology of the cell.

[78]  D. Clemmons,et al.  Extracellular matrix contains insulin-like growth factor binding protein-5: potentiation of the effects of IGF-I , 1993, The Journal of cell biology.

[79]  G. Semenza,et al.  Life with Oxygen , 2007, Science.

[80]  S. E. Knowles,et al.  Insulin-like growth factor-I (IGF-I) and especially IGF-I variants are anabolic in dexamethasone-treated rats. , 1992, The Biochemical journal.

[81]  C. M. Nolan,et al.  Zebrafish insulin-like growth factor-I receptor: molecular cloning and developmental expression , 2002, Molecular and Cellular Endocrinology.

[82]  A. Musarò,et al.  Muscle-specific expression of insulin-like growth factor I counters muscle decline in mdx mice , 2002, The Journal of cell biology.

[83]  R. Bruick,et al.  Oxygen sensing in the hypoxic response pathway: regulation of the hypoxia-inducible transcription factor. , 2003, Genes & development.

[84]  Harold Weintraub,et al.  The MyoD family and myogenesis: Redundancy, networks, and thresholds , 1993, Cell.

[85]  张哉根,et al.  Leu-M , 1991 .

[86]  P. Yamada,et al.  Perspectives in mammalian IGFBP-3 biology: local vs. systemic action. , 2009, American journal of physiology. Cell physiology.

[87]  C. Stewart,et al.  Insulin-like growth factor binding protein-5 modulates muscle differentiation through an insulin-like growth factor-dependent mechanism , 1996, The Journal of cell biology.

[88]  C. Woods,et al.  Somatic overgrowth associated with overexpression of insulin–like growth factor II , 1996, Nature Medicine.

[89]  P. Rotwein,et al.  Rapid activation of insulin-like growth factor binding protein-5 gene transcription during myoblast differentiation. , 1995, Molecular endocrinology.

[90]  M. Rudnicki,et al.  The emerging biology of satellite cells and their therapeutic potential. , 2008, Trends in molecular medicine.

[91]  M. Savage,et al.  Intrauterine growth retardation and postnatal growth failure associated with deletion of the insulin-like growth factor I gene. , 1996, The New England journal of medicine.

[92]  E. Zwarthoff,et al.  Mutations in the C-terminal part of insulin-like growth factor (IGF)-binding protein-1 result in dimer formation and loss of IGF binding capacity. , 1991, Molecular endocrinology.

[93]  M. Stoffel,et al.  β-cell–specific deletion of the Igf1 receptor leads to hyperinsulinemia and glucose intolerance but does not alter β-cell mass , 2002, Nature Genetics.

[94]  C. Avendaño,et al.  Delayed Inner Ear Maturation and Neuronal Loss in PostnatalIgf-1-Deficient Mice , 2001, The Journal of Neuroscience.

[95]  C. Duan,et al.  Insulin-like Growth Factor-binding Protein-3 Plays an Important Role in Regulating Pharyngeal Skeleton and Inner Ear Formation and Differentiation* , 2005, Journal of Biological Chemistry.

[96]  E. D. De Robertis,et al.  Neural and head induction by insulin-like growth factor signals. , 2001, Developmental cell.

[97]  J. Florini,et al.  The Mitogenic and Myogenic Actions of Insulin-like Growth Factors Utilize Distinct Signaling Pathways* , 1997, The Journal of Biological Chemistry.

[98]  T. Wood,et al.  Selective alterations in organ sizes in mice with a targeted disruption of the insulin-like growth factor binding protein-2 gene. , 2000, Molecular endocrinology.

[99]  A. Musarò,et al.  Viral mediated expression of insulin-like growth factor I blocks the aging-related loss of skeletal muscle function. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[100]  C. M. Nolan,et al.  Insulin-like growth factor (IGF) signalling is required for early dorso-anterior development of the zebrafish embryo. , 2004, The International journal of developmental biology.

[101]  M. Buckingham,et al.  The formation of skeletal muscle: from somite to limb , 2003, Journal of anatomy.

[102]  L. Donahue,et al.  Targeted overexpression of insulin-like growth factor I to osteoblasts of transgenic mice: increased trabecular bone volume without increased osteoblast proliferation. , 2000, Endocrinology.

[103]  D. Accili,et al.  Hypoxia converts the myogenic action of insulin-like growth factors into mitogenic action by differentially regulating multiple signaling pathways , 2010, Proceedings of the National Academy of Sciences.

[104]  S. Bayol,et al.  Phenotypic expression of IGF binding protein transcripts in muscle, in vitro and in vivo. , 2000, Biochemical and biophysical research communications.

[105]  R. Hovorka,et al.  IGF-I treatment in adults with type 1 diabetes: effects on glucose and protein metabolism in the fasting state and during a hyperinsulinemic-euglycemic amino acid clamp. , 2000, Diabetes.

[106]  A. Moses,et al.  Recombinant Human Insulin-Like Growth Factor I Increases Insulin Sensitivity and Improves Glycemic Control in Type II Diabetes , 1996, Diabetes.

[107]  T. Maures,et al.  Structural, biochemical, and expression analysis of two distinct insulin-like growth factor I receptors and their ligands in zebrafish. , 2002, Endocrinology.

[108]  L. Bach,et al.  The N-terminal Disulfide Linkages of Human Insulin-like Growth Factor-binding Protein-6 (hIGFBP-6) and hIGFBP-1 Are Different as Determined by Mass Spectrometry* , 1999, The Journal of Biological Chemistry.

[109]  F. Gage,et al.  Retrograde Viral Delivery of IGF-1 Prolongs Survival in a Mouse ALS Model , 2003, Science.

[110]  S. Kornfeld.  Structure and function of the mannose 6-phosphate/insulinlike growth factor II receptors. , 1992, Annual review of biochemistry.

[111]  M. White,et al.  Insulin-like signaling, nutrient homeostasis, and life span. , 2008, Annual review of physiology.

[112]  C. Duan,et al.  Roles of insulin-like growth factor (IGF) binding proteins in regulating IGF actions. , 2005, General and comparative endocrinology.

[113]  P. Yin,et al.  Several Acidic Amino Acids in the N-domain of Insulin-like Growth Factor-binding Protein-5 Are Important for Its Transactivation Activity* , 2006, Journal of Biological Chemistry.

[114]  Christophe Héligon,et al.  The IGF pathway regulates head formation by inhibiting Wnt signaling in Xenopus. , 2002, Developmental biology.

[115]  C. Stewart,et al.  Overexpression of insulin‐like growth factor‐II induces accelerated myoblast differentiation , 1996, Journal of cellular physiology.

[116]  G R Hunter,et al.  Mechanical load increases muscle IGF-I and androgen receptor mRNA concentrations in humans. , 2001, American journal of physiology. Endocrinology and metabolism.

[117]  Bao Hoang,et al.  Delayed mammary gland involution in mice with mutation of the insulin-like growth factor binding protein 5 gene. , 2007, Endocrinology.

[118]  M. Lawlor,et al.  Dual Control of Muscle Cell Survival by Distinct Growth Factor-Regulated Signaling Pathways , 2000, Molecular and Cellular Biology.

[119]  C. Emerson.  Skeletal myogenesis: genetics and embryology to the fore. , 1993, Current opinion in genetics & development.

[120]  P. De Meyts,et al.  Structural biology of insulin and IGF-1 receptors. , 2004, Novartis Foundation symposium.

[121]  D. Clemmons,et al.  Use of mutagenesis to probe IGF-binding protein structure/function relationships. , 2001, Endocrine reviews.

[122]  M. Tremblay,et al.  Inactivation of the acid labile subunit gene in mice results in mild retardation of postnatal growth despite profound disruptions in the circulating insulin-like growth factor system. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[123]  J. Baker,et al.  Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r) , 1993, Cell.

[124]  D. Steiner,et al.  Gene duplication and functional divergence of the zebrafish insulin‐like growth factor 1 receptors , 2006, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[125]  M. Bouxsein,et al.  Osteoblast-specific Knockout of the Insulin-like Growth Factor (IGF) Receptor Gene Reveals an Essential Role of IGF Signaling in Bone Matrix Mineralization* , 2002, The Journal of Biological Chemistry.

[126]  G. Schuler,et al.  Effects of exercise training on insulin-like growth factor-I expression in the skeletal muscle of non-cachectic patients with chronic heart failure , 2005, European journal of cardiovascular prevention and rehabilitation : official journal of the European Society of Cardiology, Working Groups on Epidemiology & Prevention and Cardiac Rehabilitation and Exercise Physiology.

[127]  P. Yin,et al.  Evidence That IGF Binding Protein-5 Functions as a Ligand-Independent Transcriptional Regulator in Vascular Smooth Muscle Cells , 2004, Circulation research.

[128]  S. Yakar,et al.  The somatomedin hypothesis: 2001. , 2001, Endocrine reviews.

[129]  E. Ayuso,et al.  β cell expression of IGF-I leads to recovery from type 1 diabetes , 2002 .

[130]  H. M. El-Shewy,et al.  The Insulin-like Growth Factor Type 1 and Insulin-like Growth Factor Type 2/Mannose-6-phosphate Receptors Independently Regulate ERK1/2 Activity in HEK293 Cells* , 2007, Journal of Biological Chemistry.

[131]  J. Wallace,et al.  Alanine Screening Mutagenesis Establishes Tyrosine 60 of Bovine Insulin-like Growth Factor Binding Protein-2 as a Determinant of Insulin-like Growth Factor Binding* , 1998, The Journal of Biological Chemistry.

[132]  P. Vogt,et al.  Myogenic signaling of phosphatidylinositol 3-kinase requires the serine-threonine kinase Akt/protein kinase B. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[133]  P. Rotwein,et al.  A highly conserved insulin-like growth factor-binding protein (IGFBP-5) is expressed during myoblast differentiation. , 1993, Journal of Biological Chemistry.

[134]  Jianfeng Zhou,et al.  Duplication of the IGFBP-2 Gene in Teleost Fish: Protein Structure and Functionality Conservation and Gene Expression Divergence , 2008, PloS one.

[135]  S. Mohan,et al.  Insulin-like growth factor-binding proteins in serum and other biological fluids: regulation and functions. , 1997, Endocrine reviews.

[136]  R. Radulescu.  From insulin, retinoblastoma protein and the insulin receptor to a new model on growth factor specificity: the nucleocrine pathway. , 1995, The Journal of endocrinology.

[137]  D. Clemmons,et al.  Regulation of Vascular Smooth Muscle Cell Responses to Insulin-like Growth Factor (IGF)-I by Local IGF-binding Proteins* , 2003, Journal of Biological Chemistry.