Pathway maps

Development_IGF-1 receptor signaling
Development_IGF-1 receptor signaling

Object List (links open in MetaCore):

RHEB2, 14-3-3 beta/alpha, UDP-D-glucose cytosol, IGF-2, p90Rsk, MEK2 (MAP2K2), c-Myc, IRS-1, PtdIns(3,4,5)P3, PtdIns(4,5)P2, IKK (cat), Erk (MAPK1/3), Hamartin, c-Raf-1, AKT (PKB), PI3K cat class IA, ASK1 (MAP3K5), c-Raf-1, 14-3-3 epsilon, PTEN, 14-3-3 zeta/delta, IGF-1, PI3K reg class IA, p70 S6 kinase1, CREB1, GSK3 alpha/beta, Cyclin D, 3.1.3.67, MEK1 (MAP2K1), Bcl-XL, GRB2, PDK (PDPK1), mTOR, Caspase-9, FOXO3A, Tuberin, 2.7.1.137, Glycogen, I-kB, BAD, 4E-BP1, IGF-1 receptor, H-Ras, IBP, IKK-alpha, GYS1, 2.4.1.11, RPS6, Shc, SOS, NF-kB, Elk-1

Description

IGF-R1 signaling

The insulin-like growth factor system (IGF system) comprises two receptors: Insulin-like growth factor 1 receptor ( IGF-1 receptor ) and IGF-IIR with their respective ligands: Insulin-like growth factors 1 and 2 ( IGF-1 and IGF-2 ) and six high-affinity IGF binding proteins ( IBP ).

The principal processes mediated by the IGF system include stimulation of somatic growth by promoting cellular proliferation and differentiation. Additionally, it was shown that signaling through the IGF-1 receptor plays a critical role in cell survival and prevention of programmed cell death. In contrast, the IGF-IIR does not appear to be involved in the regulation of apoptosis [1].

Both IGF-1 and IGF-2 exhibit the high-affinity binding to IGF-1 receptor. The IGF binding proteins ( IBP ) bind to both IGF-1 and IGF-2 with high-affinity. Their main role is to modulate actions of free IGF-1 and IGF-2 [2], [1].

IGF-1 receptor is a transmembrane tyrosine kinase receptor that is highly homologous to the insulin receptor (IR). Like IR, IGF-1 receptor consists of a2b2 heterotetramers held together by disulfide bridges [1]. IGF-1 receptor and IR can also form heterodimers.

Binding of IGF-1 and IGF-2 to the cognate IGF-1 receptor stimulates the intrinsic tyrosine kinase activity of this receptor [1].

Upon IGF binding, the tyrosine kinase activity of IGF-1 receptor leads to the phosphorylation of several substrates, including the insulin receptor substrate family of proteins (such as Insulin receptor substrate 1 ( IRS-1 )), SHC (Src homology 2 domain containing) transforming protein 1 ( Shc ) and some others [3], [4].

Once phosphorylated, these docking proteins activate downstream intracellular signaling through the Phosphatidylinositol 3-kinase ( PI3K ) or Growth factor receptor-bound protein 2 ( GRB2 )/ Son of sevenless homolog ( SOS )/ v-Ha-ras Harvey rat sarcoma viral oncogene homolog ( H-Ras ) pathways that ultimately leads to cellular proliferation [3], [4].

Activation of IGF-1 receptor by its ligand also initiates metabolic cascades that result in the stimulation of protein synthesis via activation of Ribosomal protein S6 kinase, 70kDa, polypeptide 1 ( p70 S6 kinase 1 ), glucose uptake, glycogen synthesis, and lipid storage [4].

As mentioned above, IGF-1 and IGF-2 exhibit strong anti-apoptotic activity. There are three IGF-1 receptor -induced anti-apoptotic pathways. The main pathway for the antiapoptotic effect stimulated by IGF-1 receptor is the well-established IRS-1 -mediated pathway that causes activation of PI3K and V-akt murine thymoma viral oncogene homolog 1 ( AKT(PKB) ), that leads to the phosphorylation of BCL2-associated agonist of cell death ( BAD ) [5].

BAD is known to be a heterodimeric partner for both BCL2-like 1 ( Bcl-XL ) and B-cell CLL/lymphoma 2 ( Bcl-2 ). BAD neutralizes Bcl-XL and Bcl-2 protective effect and promotes cell death.

In its phosphorylated form, BAD is sequestered in the cytosol by 14-3-3 proteins and cannot bind to antiapoptotic proteins of the Bcl-2 family and therefore cannot induce cell death [5].

Another known anti-apoptotic pathway is mediated by 14-3-3 proteins.

Three members of the 14-3-3 family of proteins (Tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, beta, zeta and epsilon polypeptides ( 14-3-3 beta/alpha, 14-3-3 zeta/delta, and 14-3-3 epsilon ) interact with the IGF-1 receptor, after its autophosphorilation, in a variety of cultured cell types [6].

The 14-3-3 proteins have been implicated in the activation of v-raf-1 murine leukemia viral oncogene homolog 1 ( c-Raf-1 ) [7], [8].

IGF-1 signaling leads to activation of c-Raf-1 to promote its translocation to the mitochondria, where mitochondrial c-Raf-1 phosphorylates BAD, causing its dissociation from antiapoptotic proteins (such as Bcl-2 and Bcl-XL ) and its release into the cytosol [5], [6].

Additionally, IGF-1 receptor signaling suppresses the Mitogen-activated protein kinase kinase kinase 5 ( ASK1 (MAP3K5) )-mediated stimulation of JNK/p38 and the induction of programmed cell death. ASK1 (MAP3K5) forms a complex with IGF-1 receptor. IGF-1 receptor specifically phosphorylates and inhibits ASK1 (MAP3K5). [4].

IRS proteins, including IRS -3 and IRS-4 however have a negative effect on the anti-apoptotic effects of IGF-1 [9].

References:

  1. Vincent AM, Feldman EL
    Control of cell survival by IGF signaling pathways. Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society 2002 Aug;12(4):193-7
  2. Baxter RC
    Insulin-like growth factor (IGF)-binding proteins: interactions with IGFs and intrinsic bioactivities. American journal of physiology. Endocrinology and metabolism. 2000 Jun;278(6):E967-76
  3. 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
  4. Galvan V, Logvinova A, Sperandio S, Ichijo H, Bredesen DE
    Type 1 insulin-like growth factor receptor (IGF-IR) signaling inhibits apoptosis signal-regulating kinase 1 (ASK1). The Journal of biological chemistry 2003 Apr 11;278(15):13325-32
  5. Peruzzi F, Prisco M, Dews M, Salomoni P, Grassilli E, Romano G, Calabretta B, Baserga R
    Multiple signaling pathways of the insulin-like growth factor 1 receptor in protection from apoptosis. Molecular and cellular biology 1999 Oct;19(10):7203-15
  6. Parvaresch S, Yesilkaya T, Baer K, Al-Hasani H, Klein HW
    14-3-3 binding to the IGF-1 receptor is mediated by serine autophosphorylation. FEBS letters 2002 Dec 18;532(3):357-62
  7. Thorson JA, Yu LW, Hsu AL, Shih NY, Graves PR, Tanner JW, Allen PM, Piwnica-Worms H, Shaw AS
    14-3-3 proteins are required for maintenance of Raf-1 phosphorylation and kinase activity. Molecular and cellular biology 1998 Sep;18(9):5229-38
  8. Fu H, Subramanian RR, Masters SC
    14-3-3 proteins: structure, function, and regulation. Annual review of pharmacology and toxicology 2000;40:617-47
  9. Tseng YH, Ueki K, Kriauciunas KM, Kahn CR
    Differential roles of insulin receptor substrates in the anti-apoptotic function of insulin-like growth factor-1 and insulin. The Journal of biological chemistry 2002 Aug 30;277(35):31601-11