Pathway Map Details

Transcription_Receptor-mediated HIF regulation

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Object list (links open in MetaCore):

PDK (PDPK1), insulin, IRS-4, MNK2(GPRK7), IGF-1, IRS-1, p70 S6 kinase2, SOS, HIF-1, tuberin, Grb2, PI3K cat class IA, H-Ras,, MEK1(MAP2K1), IBP3, p70 S6 kinase1, 4E-BP1, VEGF-A, IGF-1 receptor, PI3K reg class IA, Shc, IRS-2, RPS6, RHEB2, eIF4E, c-Raf-1, PKC-zeta, PI(4,5)P2,, Erk (MAPK1/3), MNK1, HIF1A, MEK2(MAP2K2), PTEN, Insulin receptor, mTOR, PI(3,4,5)P3, AKT(PKB)


Receptor-mediated HIF regulation

Insulin and Insulin-like growth factor 1 ( IGF-1 ) induce Hypoxia-inducible factor 1 alpha subunit ( HIF1A) [1], [2] and HIF-induced Vascular endothelial growth factor ( VEGF ) expression [3], [1], [2] and Insulin-like growth factor binding protein 3 ( IBP3 ) [4].

IGF-1 induces HIF1A protein synthesis via Mitogen-activated protein kinase 1 and 3 ( Erk (MAPK1/3) ) and Phosphoinositide-3-kinase ( PI3K )-dependent pathway that can involve Eukaryotic translation initiation factor 4E ( eIF4E ), Ribosomal protein S6 kinase 70kDa polypeptide (for example p70 S6 kinase2 ) [5] and 3-phosphoinositide dependent protein kinase-1 ( PDK (PDPK1) )-dependent activation of FK506 binding protein 12-rapamycin associated protein 1 ( mTOR ) [1]. IGF-1 binds IGF-1 receptor which possesses tyrosine kinase activity. IGF-1 receptor phosphorylates Insulin receptor substrate ( IRS ) and then IGF-1 receptor causes the sequential phosphorylation of PI3K, PDK, V-akt murine thymoma viral oncogene homolog 1 ( AKT(PKB) ), and mTOR. PI3K and PDK activation mediate IGF-1 -induced activation of p70 S6 kinase2 [6], [7]. Recruitment to both IRS-1 and SHC transforming protein 1 ( Shc ) via the SH2 domain of the adaptor Growth factor receptor-bound protein 2 ( Grb2 ) leads to possible activation of V-Ha-ras Harvey rat sarcoma viral oncogene homolog ( H-Ras ) that in turn activates the protein serine kinase, possibly the V-raf-1 murine leukemia viral oncogene homolog 1 ( c-Raf-1 ), and ERK cascade [7]. And then, via MAP kinase interacting serine/threonine kinase ( MNK ) and eIF4E, IGF-1 receptor induces HIF1A protein synthesis [5].

Insulin stimulates HIF1A through PI3K/ mTOR -dependent signaling pathway [8], [1]. The binding of Insulin to the extracellular domain of the Insulin receptor results in the activation of the tyrosine kinase activity of the receptor. Insulin receptor via IRS activates the same PI3K -pathway as described above [9].


  1. Treins C, Murdaca J, Van Obberghen E, Giorgetti-Peraldi S
    AMPK activation inhibits the expression of HIF-1alpha induced by insulin and IGF-1. Biochemical and biophysical research communications 2006 Apr 21;342(4):1197-202
  2. Zhou Q, Liu LZ, Fu B, Hu X, Shi X, Fang J, Jiang BH
    Reactive oxygen species regulate insulin-induced VEGF and HIF-1alpha expression through the activation of p70S6K1 in human prostate cancer cells. Carcinogenesis 2007 Jan;28(1):28-37
  3. Abraham D, Krenn K, Seebacher G, Paulus P, Klepetko W, Aharinejad S
    Upregulated hypoxia-inducible factor-1 DNA binding activity to the vascular endothelial growth factor-A promoter mediates increased vascular permeability in donor lung grafts. The Annals of thoracic surgery 2004 May;77(5):1751-5
  4. Slomiany MG, Rosenzweig SA
    IGF-1-induced VEGF and IGFBP-3 secretion correlates with increased HIF-1 alpha expression and activity in retinal pigment epithelial cell line D407. Investigative ophthalmology & visual science 2004 Aug;45(8):2838-47
  5. Fukuda R, Hirota K, Fan F, Jung YD, Ellis LM, Semenza GL
    Insulin-like growth factor 1 induces hypoxia-inducible factor 1-mediated vascular endothelial growth factor expression, which is dependent on MAP kinase and phosphatidylinositol 3-kinase signaling in colon cancer cells. The Journal of biological chemistry 2002 Oct 11;277(41):38205-11
  6. Kuemmerle JF
    IGF-I elicits growth of human intestinal smooth muscle cells by activation of PI3K, PDK-1, and p70S6 kinase. American journal of physiology. Gastrointestinal and liver physiology. 2003 Mar;284(3):G411-22
  7. Laviola L, Natalicchio A, Giorgino F
    The IGF-I signaling pathway. Current pharmaceutical design 2007;13(7):663-9
  8. Treins C, Giorgetti-Peraldi S, Murdaca J, Semenza GL, Van Obberghen E
    Insulin stimulates hypoxia-inducible factor 1 through a phosphatidylinositol 3-kinase/target of rapamycin-dependent signaling pathway. The Journal of biological chemistry 2002 Aug 2;277(31):27975-81
  9. Proud CG
    Regulation of protein synthesis by insulin. Biochemical Society transactions 2006 Apr;34(Pt 2):213-6