Affinage

IGF1

Insulin-like growth factor 1 · UniProt P05019

Length
195 aa
Mass
21.8 kDa
Annotated
2026-06-10
100 papers in source corpus 25 papers cited in narrative 25 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IGF-I (IGF1) is a secreted growth factor essential for embryonic and postnatal somatic growth and a broad effector of cell survival, proliferation, differentiation, and tissue-specific anabolic programs; genetic ablation in mice produces severe growth retardation, muscle underdevelopment, and near-complete perinatal lethality (PMID:8276243). IGF-I acts through the IGF-I receptor (IGF-IR), a tyrosine kinase that upon ligand binding autophosphorylates and recruits the adaptor substrates IRS-1 and Shc; the submembrane Tyr950 residue is critical for downstream signal transduction, and kinase-dead receptor mutants act as dominant negatives (PMID:8701079). IRS-1 is the principal node that determines the output of receptor activation: it routes signaling into PI3K/Akt-driven mitogenic and anti-apoptotic responses, with IRS-1 abundance functioning as a switch between mitogenic/survival and differentiation programs (PMID:10579905), and it additionally controls receptor trafficking by competing with the clathrin adaptor AP2 to delay IGF-IR endocytosis and sustain Akt activation (PMID:29661273). Akt is the required survival effector in multiple cell types, acting in part through GSK3beta inactivation and caspase suppression (PMID:11162904, PMID:15845077), and IGF-IR also engages anti-apoptotic outputs that are PI3K-independent (PMID:10226786). Through these pathways IGF-I directs tissue programs including pubertal mammary ductal morphogenesis as the local mediator of GH action (PMID:10791764), pancreatic beta-cell regeneration and protection (PMID:11994404), oligodendrocyte fate specification via BMP inhibition (PMID:14709544), corticospinal motor neuron axon outgrowth (PMID:17057708), and metabolic insulin-like actions including suppression of hepatic glucose output and protein catabolism (PMID:8279537). In bone, IGF-IR is required for the anabolic actions of PTH in osteoblasts (PMID:17539737) and directly phosphorylates PTH1R on Tyr494 to drive actin polymerization during the osteoblast-to-osteocyte transition (PMID:29507819), and it scaffolds GH-induced STAT5 signaling in a partly kinase-independent manner (PMID:20133448). Chronic IGF-I signaling can also drive cellular senescence through a ROS/p53/p21 pathway (PMID:22877754).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1993 High

    Established that IGF-I is an essential, non-redundant growth factor in vivo rather than merely a permissive systemic hormone, answering whether endogenous IGF-I is required for normal development.

    Evidence Homologous-recombination IGF-I knockout mice with histopathology

    PMID:8276243

    Open questions at the time
    • Does not separate embryonic from postnatal IGF-I requirement
    • Does not identify which tissues require autocrine vs endocrine IGF-I
    • Receptor and downstream effector not addressed
  2. 1993 High

    Demonstrated that IGF-I exerts direct insulin-like metabolic and protein-anabolic effects in humans, distinguishing its acute metabolic actions from chronic growth-promoting roles.

    Evidence Euglycemic clamp with stable isotope tracer kinetics in healthy men

    PMID:8279537

    Open questions at the time
    • Does not resolve whether effects are via IGF-IR or insulin receptor cross-reactivity
    • Tissue-level glucose flux mechanism not dissected
  3. 1996 High

    Defined the receptor-proximal signaling architecture, showing IGF-IR kinase activity, IRS-1 phosphorylation, and the critical submembrane Tyr950 residue transduce IGF-I signals, with a dominant-negative receptor blocking output.

    Evidence Stable transfection of WT and mutant IGF-I receptor constructs in GH-secreting cells with structure-function mutagenesis

    PMID:8701079

    Open questions at the time
    • Tested mainly in pituitary GH-secreting cells
    • Does not enumerate the full set of downstream branches
  4. 1999 Medium

    Resolved how a single receptor produces divergent outputs by identifying IRS-1 concentration as a switch between mitogenic/survival (PI3K) and differentiation pathways, and revealing a PI3K-independent anti-apoptotic arm unique to IGF-IR.

    Evidence IGF-IR-null R-cell reconstitution with IRS-1 manipulation and PI3K-inhibitor pathway dissection

    PMID:10226786 PMID:10579905

    Open questions at the time
    • Molecular identity of the PI3K-independent anti-apoptotic effector not defined
    • Single-lab cell-line model, not validated in vivo
  5. 2002 High

    Connected IGF-I to multiple tissue-specific programs—mammary ductal morphogenesis (as local mediator of GH), beta-cell regeneration, microglial proliferation, and Schwann cell survival/motility via Akt—establishing IGF-I as a broadly acting autocrine/paracrine effector.

    Evidence IGF-I KO with hormone rescue, beta-cell-specific transgenic STZ model, microglial thymidine incorporation, and dominant-negative Akt in Schwann cells

    PMID:10791764 PMID:11162904 PMID:11994404 PMID:12112378

    Open questions at the time
    • Tissue-specific signaling branches not uniformly mapped
    • Microglial and Schwann cell findings are single-lab
    • Lipid-raft/caveolin-1 mechanism (12135605) not integrated into a functional output
  6. 2005 Medium

    Defined neuronal mechanisms of IGF-I action, showing Akt/GSK3beta-mediated neuroprotection in hypoxia-ischemia and redundant MAPK+PI3K survival signaling in motor neurons, plus TRPV1 sensitization/trafficking.

    Evidence Neonatal HI rat model, primary motor neuron cultures with pathway inhibitors, and patch-clamp electrophysiology

    PMID:15193297 PMID:15845077 PMID:15857517

    Open questions at the time
    • Relative contribution of each pathway in vivo unresolved
    • Single-lab studies for each readout
  7. 2006 Medium

    Showed IGF-I drives oligodendrocyte fate via BMP inhibition and instructs corticospinal motor neuron axon outgrowth, separating its developmental/regenerative roles from generic survival support.

    Evidence Adult neural progenitor fate assays with BMP analysis and purified CSMN cultures with IGF-IR inhibition plus in vivo corroboration

    PMID:14709544 PMID:17057708

    Open questions at the time
    • Downstream effectors of BMP inhibition not fully defined
    • Mechanism linking IGF-IR to axon-outgrowth machinery unmapped
  8. 2010 High

    Revealed kinase-independent and trafficking-level functions of the receptor system: IGF-IR scaffolds GH-induced STAT5 signaling independent of its kinase, and IRS-1 delays IGF-IR endocytosis via AP2 competition to sustain Akt signaling.

    Evidence Conditional IGF-IR deletion with truncation-mutant rescue in osteoblasts; reciprocal Co-IP, AP2-binding-deficient IRS-1 mutant and single-molecule imaging

    PMID:20133448 PMID:29661273

    Open questions at the time
    • Structural basis of the kinase-independent scaffold not determined
    • Generality of the AP2-competition mechanism beyond the tested system unclear
  9. 2018 High

    Established IGF-IR as a bone anabolic hub: required for PTH anabolic action in osteoblasts, directly phosphorylating PTH1R Y494 to drive actin polymerization in the osteoblast-to-osteocyte transition, and coordinating AMPK/autophagy-dependent osteoblast differentiation.

    Evidence Osteoblast-specific IGF-IR/PTH1R conditional KO mice, in vitro kinase assay with Y494 mutagenesis, and AMPK manipulation with autophagy readouts

    PMID:17539737 PMID:26556533 PMID:29507819 PMID:8203509

    Open questions at the time
    • How IGF-IR–PTH1R crosstalk integrates with canonical PTH GPCR signaling not fully defined
    • Temporal AMPK switch mechanism incompletely resolved
  10. 2015 Medium

    Identified a detrimental face of chronic IGF-I signaling—induction of cellular senescence through a ROS/p53/p21 pathway—and a suppressive role in aging neurogenesis via Akt in neural stem cells.

    Evidence Primary cells with ROS scavenger and p53-null MEFs; conditional IGF-IR deletion in adult NSCs with fate tracing

    PMID:22877754 PMID:26219530

    Open questions at the time
    • Mechanism generating ROS downstream of IGF-I not defined
    • Reconciliation of pro-survival vs pro-senescence outputs context-dependence unresolved
  11. 2013 Medium

    Extended IGF-IR function to receptor crosstalk in disease, showing it forms a physical/functional complex with TSHR in orbital fibroblasts and exerts kinase-independent, GPCR-like activity in thyroid eye disease.

    Evidence Anti-IGF-IR antibody (teprotumumab) attenuation and IGF-IR knockdown in fibrocyte assays

    PMID:35167695

    Open questions at the time
    • Direct biochemical demonstration of the TSHR–IGF-IR complex not provided in this synthesis
    • Structural basis of the hybrid receptor behavior unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How IGF-I/IGF-IR signaling dynamics are decoded to select among opposing cell fates—survival, proliferation, differentiation, and senescence—across different tissues remains unresolved.
  • No unified model linking signal duration/amplitude to fate choice
  • Tissue-specific effector complements not comprehensively mapped
  • Structural mechanism of kinase-independent receptor scaffolding undetermined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 4 GO:0060089 molecular transducer activity 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005576 extracellular region 4 GO:0005886 plasma membrane 1
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 4 R-HSA-5357801 Programmed Cell Death 3 R-HSA-1430728 Metabolism 2 R-HSA-8953897 Cellular responses to stimuli 1
Partners
AP2CAV1IGF1RIRS1PTH1RSHC1TSHR

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 IGF-I gene knockout in mice (homologous recombination in ES cells) demonstrates IGF-I is required for normal embryonic growth: IGF-I-/- mice are <60% body weight at birth with severe muscle underdevelopment and >95% perinatal lethality, establishing IGF-I as an essential embryonic growth factor. Homologous recombination knockout mouse, histopathology Genes & development High 8276243
1993 Recombinant human IGF-I infusion in healthy men suppresses hepatic glucose output (rate of appearance), increases peripheral glucose disposal (rate of disappearance), suppresses beta-cell insulin secretion, and reduces leucine rate of appearance (protein catabolism), demonstrating direct insulin-like and protein-anabolic metabolic actions in vivo. Euglycemic clamp with stable isotope tracer kinetics (L-[1-13C]leucine, [3-3H]glucose) in humans The American journal of physiology High 8279537
1996 In the pituitary, IGF-I binds its cell-surface receptor, activates intrinsic beta-subunit tyrosine kinase, phosphorylates IRS-1, and selectively inhibits GH gene transcription and secretion; the submembrane Tyr950 residue is critical for transducing the IGF-I suppression signal to the GH gene. A kinase-deficient truncated IGF-I receptor (952STOP) acts as dominant negative, blocking both GH suppression and mitogenic IGF-I signals. Stable transfection of wild-type and mutant IGF-I receptor constructs in GH-secreting cells; structure-function mutagenesis; dominant-negative receptor analysis Recent progress in hormone research High 8701079
1999 IGF-I receptor signals through IRS-1 to activate PI3-kinase in a mitogenic/anti-apoptotic mode; in the absence of IRS-1, IGF-IR signals instead through a differentiation pathway (granulocytic differentiation in haematopoietic cells), establishing IRS-1 concentration as a switch between mitogenic/survival and differentiation outputs of the IGF-IR. Cell-based assays with IRS-1 manipulation (overexpression and loss-of-function) in R-cell (IGF-IR-null MEF) system; IGF-IR reconstitution Experimental cell research Medium 10579905
1999 IGF-IR protects cells from apoptosis (anoikis, okadaic acid) more efficiently than the insulin receptor even when IRS-1 is overexpressed; moreover, IGF-IR anti-apoptotic signaling is resistant to PI3-kinase inhibitors, whereas insulin receptor anti-apoptotic signaling is PI3K-sensitive, revealing a PI3K-independent anti-apoptotic pathway unique to the IGF-IR. Stable transfection of IR into IGF-IR-null R-cells; apoptosis assays; PI3-kinase inhibitor treatment Hormone and metabolic research Medium 10226786
2000 IGF-I is required for pubertal mammary gland development (terminal end bud formation and ductal morphogenesis): IGF-I-/- knockout mice have grossly impaired mammary development, restored by IGF-I + estradiol treatment but not by GH + estradiol, demonstrating that GH acts through locally produced IGF-I for this developmental process. IGF-I knockout mouse model; hormone replacement experiments (IGF-I vs GH + estradiol) Journal of mammary gland biology and neoplasia High 10791764
2002 IRS-1 acts as an endocytic regulator of the IGF-I receptor by interacting with the clathrin adaptor complex AP2 and inhibiting recruitment of IGF-IR into clathrin-coated structures, thereby delaying IGF-IR endocytosis after ligand stimulation and prolonging sustained Akt activation; loss of IRS-1 shifts IGF-I signaling from sustained to transient Akt activation and augments FoxO-mediated transcription. Co-immunoprecipitation (IRS-1/AP2 interaction); endocytosis assays; AP2-binding-deficient IRS-1 mutant; single-molecule imaging; IRS-1 depletion with signaling readouts eLife High 29661273
2002 IGF-I is an autocrine/paracrine mitogen for brain microglia: IGF-I mRNA is expressed by microglia/macrophages in ischemic brain regions, and exogenous IGF-I stimulates a 2-fold increase in DNA synthesis in purified adult brain microglial cultures, establishing IGF-I as a mitogenic signal for these cells after injury. In vitro [3H]-thymidine incorporation in purified adult brain microglia; combined immunostaining/in situ hybridization in vivo Glia Medium 12112378
2002 Beta-cell-specific expression of IGF-I in transgenic mice counteracts streptozotocin-induced cytotoxicity and insulitis, promotes beta-cell neogenesis and replication, and restores normoglycemia, demonstrating that local IGF-I in pancreatic islets can regenerate beta-cell mass and protect against type 1 diabetes. Transgenic mouse overexpression (beta-cell-specific IGF-I); streptozotocin model; histomorphometry; metabolic measurements The Journal of clinical investigation High 11994404
2002 IGF-I promotes Schwann cell motility and survival via activation of Akt (phosphorylation at Ser473) downstream of PI3-kinase; dominant-negative K179M Akt transfection blocks both IGF-I-induced Akt phosphorylation and the pro-motility and anti-apoptotic effects, establishing Akt as a required effector. Dominant-negative Akt transfection; PI3-K inhibitor (LY294002); Akt phosphorylation Western blot; cell motility and survival assays Molecular and cellular endocrinology Medium 11162904
2002 IGF-I induces tyrosine phosphorylation of caveolin-1 at Tyr14 and causes translocation of caveolin-1 and formation of membrane patches on the plasma membrane; IGF-IR co-localizes with caveolin-1 in lipid raft-enriched fractions; this effect is IGF-I-specific and not reproduced by insulin in cells overexpressing insulin receptors. Co-fractionation/lipid raft isolation; Western blot for phospho-caveolin-1; immunofluorescence; R-cell reconstitution system Biochemical and biophysical research communications Medium 12135605
2004 In embryonic rat spinal cord motor neurons, IGF-I binds IGF-IR and activates both MAPK and PI3K/Akt pathways via phosphorylation of IRS-1 and Shc (but not IRS-2); IGF-I prevents glutamate-induced DNA fragmentation and caspase-3 cleavage; neither MAPK inhibitor (PD98059) nor PI3K inhibitor (LY294002) alone blocks neuroprotection, but both together are required, demonstrating pathway redundancy in motor neuron survival. Enriched primary motor neuron culture; pathway inhibitors; Western blot for signaling intermediates and caspase-3 cleavage; DNA fragmentation assay Neurobiology of disease Medium 15193297
2004 IGF-I instructs multipotent adult neural progenitor cells (hippocampus-derived) to differentiate into oligodendrocytes via inhibition of bone morphogenetic protein (BMP) signaling; modeling analysis indicates the effect is instructive (fate specification) rather than selective; overexpression of IGF-I in hippocampus in vivo increases oligodendrocyte markers. Adult neural progenitor cell culture; fate mapping; BMP signaling analysis; in vivo IGF-I overexpression with immunohistochemistry The Journal of cell biology Medium 14709544
2005 IGF-I enhances TRPV1-mediated membrane currents by both sensitizing the receptor and promoting translocation of TRPV1 from cytosol to plasma membrane; this effect requires PI3K and PKC-mediated phosphorylation of TRPV1, downstream of IGF-I receptor tyrosine kinase activation. Electrophysiology (patch-clamp) in heterologous expression systems and DRG neurons; PI3K and PKC inhibitors; immunofluorescence for TRPV1 localization Molecular pain Medium 15857517
2005 IGF-I neuroprotection in hypoxia-ischemia involves activation of Akt (PI3K pathway) and inactivation of GSK3beta: ICV IGF-I after HI increases pAkt in cytosol and pGSK3beta in both cytosol and nuclear fractions, concomitant with reduced caspase-3 and caspase-9 activity, resulting in 40% reduction in brain damage. Neonatal rat HI model; ICV IGF-I administration; Western blot for pAkt, pGSK3beta; caspase activity assays; immunohistochemistry The European journal of neuroscience Medium 15845077
2006 IGF-I specifically enhances the extent and rate of axon outgrowth of corticospinal motor neurons (CSMN) via the IGF-I receptor and downstream signaling pathways; this effect is distinct from IGF-I support of neuronal survival and distinct from BDNF, which promotes branching/arborization but not axon outgrowth. CSMN purification and culture; IGF-IR inhibition; in vivo analyses; comparison with BDNF Nature neuroscience High 17057708
2007 IGF-IR in mature osteoblasts is required for PTH anabolic effects on bone: osteoblast-specific IGF-IR knockout (IGF-IR OBKO) mice have reduced bone volume, decreased periosteal bone formation, and impaired PTH-stimulated osteoprogenitor cell proliferation and differentiation, establishing that PTH requires IGF-IR signaling in osteoblasts to exert its anabolic actions. Conditional (osteoblast-specific) IGF-IR knockout mice; PTH treatment; microCT; bone histomorphometry; BMSC culture Journal of bone and mineral research High 17539737
2008 IGF-I rescues diabetic cardiomyocyte dysfunction by inhibiting RhoA activation and restoring Akt phosphorylation, thereby re-coupling eNOS (reversing eNOS uncoupling indicated by NOS inhibitor-sensitive O2- accumulation), restoring NO levels, and normalizing Kv1.2 potassium channel expression and cardiomyocyte contractile parameters. IGF-I transgenic mice crossed with diabetic model; Rho kinase inhibitor (Y27632); eNOS coupler (BH4/folate); echocardiography; cardiomyocyte contractility measurements; Western blot for RhoA, pAkt, pERK, eNOS American journal of physiology. Regulatory, integrative and comparative physiology Medium 18199585
2010 IGF-IR deletion specifically in adult neural stem cells (NSCs) increases cumulative neuroblast production and enhances neuronal integration into the olfactory bulb during aging, with differential downstream effects: Akt phosphorylation preferentially decreased in IGF-1R-/- NSCs within the niche, while ERK pathway is downregulated in differentiated neurons, demonstrating that IGF-I signaling through Akt in NSCs suppresses neurogenesis during aging. Conditional IGF-IR knockout in adult NSCs; BrdU/EdU cell fate tracing; Western blot for pAkt, pERK; olfactory behavioral testing; mathematical modeling Aging cell Medium 26219530
2012 IGF-I enhances cellular senescence in confluent primary cells (mouse, rat, human) through a ROS-p53 pathway: IGF-I induces γH2AX (DNA damage marker), increases p53 and p21, and activates SA-β-gal; ROS scavenger (NAC) suppresses senescence markers; p53-null MEFs are resistant to IGF-I-induced SA-β-gal and p21 induction, establishing that p53 is required downstream of IGF-I/ROS in this pathway. Primary cell cultures (confluent state); ROS scavenger treatment; p53-null MEFs; SA-β-gal assay; Western blot for γH2AX, p53, p21 Biochemical and biophysical research communications Medium 22877754
2015 IGF-I and IGFBP-2 coordinately stimulate osteoblast differentiation through early activation of AMPK (via their respective receptors), which drives autophagy (ULK-1 S555 phosphorylation, beclin-1 and LC3II induction); early AMPK activity is required, but subsequent AMPK down-regulation is also necessary to permit mTOR/AKT activation and completion of differentiation. Calvarial osteoblast and MC-3T3 cell cultures; AMPK inhibitors; constitutively active AMPK overexpression; receptor-blocking antibodies; Western blot for autophagy markers; differentiation assays Endocrinology Medium 26556533
2018 IGF1R directly phosphorylates a specific tyrosine residue (Y494) on the cytoplasmic domain of PTH1R in vitro; phosphorylated PTH1R localizes to barbed ends of actin filaments and increases actin polymerization during osteoblast-to-osteocyte morphological transition; disruption of Y494 reduces actin polymerization and dendrite length; conditional ablation of PTH1R in osteoblasts reduces osteocyte number and dendrites per osteocyte in vivo. In vitro kinase assay (IGF1R phosphorylation of PTH1R); site-directed mutagenesis (Y494); immunofluorescence for actin and pPTH1R; conditional PTH1R KO mice Bone research High 29507819
2010 IGF-IR is required for acute GH-induced STAT5 signaling in osteoblasts: Cre-mediated deletion of IGF-IR in primary calvarial osteoblasts more than doubles the ED50 for GH-induced STAT5 activation and reduces maximal STAT5 activity by ~50%, while sparing GH-induced ERK; a C-terminally truncated IGF-IR lacking the kinase domain partially rescues GH-induced STAT5 activity, suggesting IGF-IR facilitates GH signaling through a kinase-independent scaffolding mechanism in addition to its role as IGF-I signal transducer. Adenoviral Cre-mediated conditional IGF-IR deletion in primary osteoblasts; STAT5 luciferase reporter; adenoviral IGF-IR re-expression and truncation mutant rescue; Western blot for pSTAT5, pERK Molecular endocrinology High 20133448
1994 High extracellular calcium stimulates osteoblast DNA synthesis via an autocrine/paracrine IGF-I mechanism: elevated [Ca2+]e increases IGF-I mRNA expression and IGF-I protein secretion from MC3T3-E1 osteoblastic cells; neutralizing IGF-I antiserum completely abolishes the high [Ca2+]e-induced increase in DNA synthesis. MC3T3-E1 osteoblast cell culture; [3H]-thymidine incorporation; IGF-I neutralizing antibody; Northern blot for IGF-I mRNA; IGF-I RIA The American journal of physiology Medium 8203509
2013 In thyroid eye disease (TED), IGF-IR forms a physical and functional complex with TSHR in orbital fibroblasts/fibrocytes; actions mediated through TSHR are dependent on IGF-IR activity; IGF-IR possesses kinase-independent activities and functions as a tyrosine kinase/G-protein-coupled receptor hybrid using the G-protein receptor kinase/β-arrestin system. Teprotumumab (anti-IGF-IR monoclonal antibody) attenuation of both IGF-I and TSH actions; in vitro fibrocyte assays; IGF-IR knockdown The Journal of clinical endocrinology and metabolism Medium 35167695

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1993 IGF-I is required for normal embryonic growth in mice. Genes & development 622 8276243
2003 IGF-I receptor mutations resulting in intrauterine and postnatal growth retardation. The New England journal of medicine 439 14657428
2001 Distinct and overlapping functions of insulin and IGF-I receptors. Endocrine reviews 426 11739335
2008 Regulation of muscle mass by growth hormone and IGF-I. British journal of pharmacology 321 18500379
2006 IGF-I specifically enhances axon outgrowth of corticospinal motor neurons. Nature neuroscience 287 17057708
2001 IGF-I receptor signalling in transformation and differentiation. Molecular pathology : MP 266 11376123
2004 IGF-I instructs multipotent adult neural progenitor cells to become oligodendrocytes. The Journal of cell biology 265 14709544
1999 The IGF-I receptor in cancer research. Experimental cell research 251 10579905
2007 The IGF-I signaling pathway. Current pharmaceutical design 231 17346182
2000 Function of the IGF-I receptor in breast cancer. Journal of mammary gland biology and neoplasia 200 10791772
2002 Invited Review: Autocrine/paracrine IGF-I and skeletal muscle adaptation. Journal of applied physiology (Bethesda, Md. : 1985) 181 12183514
2008 Regulation of IGF-I function by proinflammatory cytokines: at the interface of immunology and endocrinology. Cellular immunology 177 18325486
2006 IGF-I mediated survival pathways in normal and malignant cells. Biochimica et biophysica acta 159 16844299
1999 IGF-I and IGF-II in relation to colorectal cancer. International journal of cancer 159 10449601
2009 Role of IGF-I in skeletal muscle mass maintenance. Trends in endocrinology and metabolism: TEM 156 19729319
2009 The current status of IGF-I assays--a 2009 update. Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society 154 19818658
2005 Sensitization and translocation of TRPV1 by insulin and IGF-I. Molecular pain 152 15857517
2003 Mechanisms by which IGF-I may promote cancer. Cancer biology & therapy 148 14688466
2000 IGF-I: an essential factor in terminal end bud formation and ductal morphogenesis. Journal of mammary gland biology and neoplasia 141 10791764
2004 IGF-I prevents glutamate-induced motor neuron programmed cell death. Neurobiology of disease 133 15193297
2010 Toward a comprehensive neurobiology of IGF-I. Developmental neurobiology 132 20186710
2002 Signalling through IGF-I and insulin receptors: where is the specificity? Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society 131 12175645
2001 What is the role of circulating IGF-I? Trends in endocrinology and metabolism: TEM 131 11167121
2005 Mechanical signals, IGF-I gene splicing, and muscle adaptation. Physiology (Bethesda, Md.) 130 16024511
2015 Role of IGF-I signaling in muscle bone interactions. Bone 129 26453498
2006 The ABCs of IGF-I isoforms: impact on muscle hypertrophy and implications for repair. Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme 127 17213901
2002 Beta cell expression of IGF-I leads to recovery from type 1 diabetes. The Journal of clinical investigation 125 11994404
2008 Similarities and differences between insulin and IGF-I: structures, receptors, and signalling pathways. Archives of physiology and biochemistry 123 18465355
2005 IGF-I neuroprotection in the immature brain after hypoxia-ischemia, involvement of Akt and GSK3beta? The European journal of neuroscience 116 15845077
2002 IGF-I and microglia/macrophage proliferation in the ischemic mouse brain. Glia 115 12112378
2007 IGF-I receptor is required for the anabolic actions of parathyroid hormone on bone. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 111 17539737
1988 Histochemical localization of IGF-I and IGF-II mRNA in the rat between birth and adulthood. Development (Cambridge, England) 106 3253059
2004 IGF-I and breast cancer: a meta-analysis. International journal of cancer 104 15221971
1999 Insulin and IGF-I receptors signaling in protection from apoptosis. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme 103 10226786
1999 Variation among cell types in the signaling pathways by which IGF-I stimulates specific cellular responses. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme 102 10226784
1996 IGF-I: a mitogen also involved in differentiation processes in mammalian cells. The international journal of biochemistry & cell biology 96 8697095
2005 Role of IGFBP2, IGF-I and IGF-II in regulating long bone growth. Bone 94 16183342
2005 Are the metabolic effects of GH and IGF-I separable? Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society 86 15701568
2007 Inflammation and IGF-I activate the Akt pathway in breast cancer. International journal of cancer 81 17096325
2013 The decline and fall of the IGF-I receptor. Journal of cellular physiology 78 22926508
2005 Cross-talk between IGF-I and TGF-beta signaling pathways. Cytokine & growth factor reviews 78 16297654
2015 IGF-I and IGFBP-2 Stimulate AMPK Activation and Autophagy, Which Are Required for Osteoblast Differentiation. Endocrinology 76 26556533
2010 IGF-I and the aging mammalian brain. Experimental gerontology 74 20863877
2006 Cross-talk between IGF-I and estradiol in the brain: focus on neuroprotection. Neuroendocrinology 72 17124377
2007 Aging impairs IGF-I receptor activation and induces skeletal resistance to IGF-I. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 69 17488198
2003 Regulation of IGF-I receptor signaling in tumor cells. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme 69 14710357
2013 Autocrine and Paracrine Actions of IGF-I Signaling in Skeletal Development. Bone research 68 26273506
2008 Clinical relevance of systemic and local IGF-I: lessons from animal models. Pediatric endocrinology reviews : PER 66 18317445
2006 Central and opposing effects of IGF-I and IGF-binding protein-3 on systemic insulin action. Diabetes 66 17003344
2000 IGF-I- and IGFBP-3-expression in cultured human preadipocytes and adipocytes. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme 66 11246824
2015 Suppression of IGF-I signals in neural stem cells enhances neurogenesis and olfactory function during aging. Aging cell 65 26219530
2010 The role of GH and IGF-I in mediating anabolic effects of testosterone on androgen-responsive muscle. Endocrinology 65 21084444
2007 IGF-I treatment of insulin resistance. European journal of endocrinology 65 17785698
2005 IGF-I is a matter of heart. Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society 64 15809013
1993 Effects of recombinant human IGF-I on glucose and leucine kinetics in men. The American journal of physiology 63 8279537
2008 IGF-I alleviates diabetes-induced RhoA activation, eNOS uncoupling, and myocardial dysfunction. American journal of physiology. Regulatory, integrative and comparative physiology 62 18199585
2008 Linking sirtuins, IGF-I signaling, and starvation. Experimental gerontology 61 18638538
2004 Evidence for a link between IGF-I and cancer. European journal of endocrinology 61 15339239
2004 Sequence of IGF-I, IGF-II, and HGF expression in regenerating skeletal muscle. Histochemistry and cell biology 59 15480739
2014 Optimizing IGF-I for skeletal muscle therapeutics. Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society 57 25002025
2018 IRS-1 acts as an endocytic regulator of IGF-I receptor to facilitate sustained IGF signaling. eLife 56 29661273
2005 Plasma IGF-I levels and cognitive performance in older women. Neurobiology of aging 55 16337715
2001 IGF-I mRNA and signaling in the diabetic retina. Diabetes 54 11147784
2000 IGF-I promotes Schwann cell motility and survival via activation of Akt. Molecular and cellular endocrinology 54 11162904
2016 The dietary protein, IGF-I, skeletal health axis. Hormone molecular biology and clinical investigation 50 26985688
2005 Control of aging and longevity by IGF-I signaling. Experimental gerontology 50 16154307
1994 IGF-I mediates the stimulatory effect of high calcium concentration on osteoblastic cell proliferation. The American journal of physiology 49 8203509
2016 IGF-I deficiency, longevity and cancer protection of patients with Laron syndrome. Mutation research. Reviews in mutation research 48 28528685
2010 Long-term IGF-I exposure decreases autophagy and cell viability. PloS one 48 20830296
1996 IGF-I receptor signalling: lessons from the somatotroph. Recent progress in hormone research 48 8701079
2002 IGF-I induces caveolin 1 tyrosine phosphorylation and translocation in the lipid rafts. Biochemical and biophysical research communications 47 12135605
1993 Insulin and IGF-I receptor signaling in cultured neurons. Annals of the New York Academy of Sciences 47 8215046
2022 It Takes Two to Tango: IGF-I and TSH Receptors in Thyroid Eye Disease. The Journal of clinical endocrinology and metabolism 46 35167695
2003 Persistent IGF-I overexpression in skeletal muscle transiently enhances DNA accretion and growth. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 46 12528713
2012 IGF-I enhances cellular senescence via the reactive oxygen species-p53 pathway. Biochemical and biophysical research communications 44 22877754
2018 IGF-I induced phosphorylation of PTH receptor enhances osteoblast to osteocyte transition. Bone research 42 29507819
1998 IGF-I and IGF-binding protein-1 are related to cortisol in human cord blood. European journal of endocrinology 42 9625363
2006 The effects of TGF-beta1 and IGF-I on the biomechanics and cytoskeleton of single chondrocytes. Osteoarthritis and cartilage 41 16824771
2000 Local IGF-I axis in peripubertal ruminant mammary development. Journal of mammary gland biology and neoplasia 41 10791767
2005 Effects of GH and IGF-I on the in vitro maturation of mouse oocytes. Hormones (Athens, Greece) 40 16613825
2003 Localization of IGF-I, IGF-I receptor, and IGFBP-2 in developing Umbrina cirrosa (Pisces: Osteichthyes). General and comparative endocrinology 39 12606266
2006 Impairment of IGF-I gene splicing and MGF expression associated with muscle wasting. The international journal of biochemistry & cell biology 38 16463438
1998 Effects of aFGF, bFGF, TGFbeta1 and IGF-I on odontoblast differentiation in vitro. European journal of oral sciences 38 9541212
2013 Stromal EGF and igf-I together modulate plasticity of disseminated triple-negative breast tumors. Cancer discovery 36 23689072
2013 IGF-I deficiency and hearing loss: molecular clues and clinical implications. Pediatric endocrinology reviews : PER 36 23957197
2021 Therapeutic IGF-I receptor inhibition alters fibrocyte immune phenotype in thyroid-associated ophthalmopathy. Proceedings of the National Academy of Sciences of the United States of America 35 34949642
2006 Intranasal administration of IGF-I improves behavior and Purkinje cell pathology in SCA1 mice. Brain research bulletin 35 16647585
2016 Therapeutic potential of IGF-I on hippocampal neurogenesis and function during aging. Neurogenesis (Austin, Tex.) 34 28405590
1993 IGF-I and the IGF-I receptor in development of nonmammalian vertebrates. Molecular reproduction and development 34 8398123
2002 Protein anabolic effects of insulin and IGF-I in the ovine fetus. American journal of physiology. Endocrinology and metabolism 33 12488244
2016 Endocrine and Local IGF-I in the Bony Fish Immune System. Biology 32 26821056
2005 Ovarian and IGF-I axis control of mammary development in prepubertal heifers. Domestic animal endocrinology 32 15998499
2003 IGF-I gene transfer by electroporation promotes regeneration in a muscle injury model. Gene therapy 32 12692589
2000 IGF-I and osteoporosis. Clinics in laboratory medicine 32 10986623
1996 Growth hormone and IGF-I therapy in the hypercatabolic patient. Bailliere's clinical endocrinology and metabolism 32 8853450
1996 Expression of IGF-I and IGF-binding protein genes in cirrhotic liver. The Journal of endocrinology 31 8708531
2013 Interaction between IGF-IR and ER induced by E2 and IGF-I. PloS one 30 23704881
2008 Changes in insulin and IGF-I receptor expression during differentiation of human preadipocytes. Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society 30 18693051
2015 Role of IGF-I in follistatin-induced skeletal muscle hypertrophy. American journal of physiology. Endocrinology and metabolism 29 26219865
2010 Deletion of IGF-I receptor (IGF-IR) in primary osteoblasts reduces GH-induced STAT5 signaling. Molecular endocrinology (Baltimore, Md.) 28 20133448

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