Development - IGF-1 receptor signaling

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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 [1], [2].

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 and 2 (IRS-1 and IRS-2)), SHC (Src homology 2 domain containing) transforming protein 1 (Shc) and some others [3], [4], [5].

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], [5].

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 [5].

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) [6].

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 [6].

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 [7].

The 14-3-3 proteins have been implicated in the activation of v-raf-1 murine leukemia viral oncogene homolog 1 (c-Raf-1) [8], [9].

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 [6], [7].

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). [5].

IRS proteins, including IRS-3 and IRS-4 however have a negative effect on the anti-apoptotic effects of IGF-1 [10].

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. Kim B, Cheng HL, Margolis B, Feldman EL
    Insulin receptor substrate 2 and Shc play different roles in insulin-like growth factor I signaling. The Journal of biological chemistry 1998 Dec 18;273(51):34543-50
  4. 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
  5. 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
  6. 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
  7. 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
  8. 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
  9. Fu H, Subramanian RR, Masters SC
    14-3-3 proteins: structure, function, and regulation. Annual review of pharmacology and toxicology 2000;40:617-47
  10. 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

  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. Kim B, Cheng HL, Margolis B, Feldman EL
    Insulin receptor substrate 2 and Shc play different roles in insulin-like growth factor I signaling. The Journal of biological chemistry 1998 Dec 18;273(51):34543-50
  4. 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
  5. 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
  6. 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
  7. 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
  8. 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
  9. Fu H, Subramanian RR, Masters SC
    14-3-3 proteins: structure, function, and regulation. Annual review of pharmacology and toxicology 2000;40:617-47
  10. 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

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