Development - Growth hormone signaling via PI3K/AKT and MAPK cascades

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Growth hormone signaling via PI3K and MAPK cascades

Growth hormone (GH or Somatotropin) is a major growth-promoting and metabolic regulatory hormone. Interaction of Somatotropin with Growth hormone receptor (GHR), by virtue of receptor dimerization, causes activation of GHR associated cytoplasmic tyrosine kinase, Janus kinase 2 (JAK2) [1].Almost all downstream signaling pathways utilized by Somatotropin require JAK2 activity [2], [3].

Somatotropin effects include stimulation of amino acid transport, protein synthesis, glucose transport, lipogenesis, gene expression, mitogenesis, prevention of apoptosis, differentiation and reorganization of cytoskeletal architecture [4].

Somatotropin activates Mitogen activated protein kinase 1 (ERK2) [5], [6] and Mitogen activated protein kinase 14 (p38alpha (MAPK14)) [7] via JAK2-associated adapter proteins Src homology 2 domain containing transforming protein 1 (Shc) and Growth factor receptor-bound protein 2 (Grb2) [8]. Somatotropin stimulation results in the assembly of a Shc-GRB2- Son of sevenless homologes (SOS) complex with the resultant activation of v-Ha-ras Harvey rat sarcoma viral oncogene homolog (H-RAS) and subsequent engagement of the -raf-1 murine leukemia viral oncogene homolog 1 (c-Raf-1)/ Mitogen-activated protein kinase kinase 1 (MEK1(MAP2K1)/ ERK2 pathway [9]. In response to Somatotropin signaling, ERK2 phosphorylates and activates several transcription factors including Activating transcription factor 2 (ATF-2), ELK1, member of ETS oncogene family (Elk-1) and ELK4, ETS-domain protein () Elk-4. Ternary complex factors Elk-1 and Elk-4 mediate Somatotropin -induced transcription of Early growth response factor-1 (EGR1), v-fos FBJ murine osteosarcoma viral oncogene homolog (c-Fos) and Jun B proto-oncogene (JunB) genes [10], [11].

Activation of p38alpha (MAPK14) by Somatotropin is the JAK2-dependent process involving PTK2B protein tyrosine kinase 2 beta (Pyk2(FAK2)) and Mitogen-activated protein kinase kinase kinase 4 (MEKK4(MAP3K4))/ Mitogen-activated protein kinase kinase 3 (MEK3(MAP2K3)) activation [12]. p38alpha (MAPK14) is required for Somatotropin -induced ATF-2, DNA-damage-inducible transcript 3 (C/EBP zeta) and CCAAT/enhancer binding protein (C/EBP), beta (C/EBPbeta) transcription activity, reorganization of the actin cytoskeleton and mitogenesis [7].

A critical transcription factor of Somatotropin action is the transcription activator C/EBPbeta that is necessary for transcription of v-fos FBJ murine osteosarcoma viral oncogene homolog (c-Fos) gene [13]. Regulation of C/EBPbeta activity is mediated both by p38alpha (MAPK14) and Phosphatidylinositol 3-kinase (PI3K)/ V-akt murine thymoma viral oncogene homolog 1 (AKT(PKB)) pathways.

Somatotropin -dependent tyrosyl phosphorylation of adaptor proteins Insulin receptor substrates 1 and 2 (IRS-1, IRS-2) by JAK2 leads to the increased association of IRS-1 with Shc/GRB2 complex, and the association of IRS-1 and IRS-2 with the Phosphoinositide-3-kinase, regulatory subunit 1 (PI3K reg class IA (p85 alpha)) and Protein tyrosine phosphatase, non-receptor type 11 (SHP-2) [14]. PI3K reg class IA (p85-alpha) can bind directly to the phosphorylated tyrosine residues at the carboxyl-terminal part of the Somatotropin receptor, providing a direct alternative route for the activation of Phosphoinositide-3-kinase, catalytic, alpha polypeptide (PI3K cat class IA (p110-alpha)) [15].

Somatotropin activates serine/threonine kinase AKT(PKB) in a PI3K-dependent manner [16]. AKT(PKB) inhibits Glycogen synthase kinase 3 beta (GSK3 beta) and attenuates its negative control of C/EBPbeta activity. PI3K/ AKT(PKB)/ GSK3 beta pathway mediates signaling between Somatotropin receptor and the nucleus, promoting activation of C/EBPbeta [17].

Somatotropin also initiates PI3K/ GSK3 beta signaling to deliver an antiapoptotic signal [16].

Somatotropin -stimulated Ribosomal protein S6 kinase, 70kDa, polypeptide 1 (p70 S6 kinase 1) activation is probably mediated through a PI3K/ AKT(PKB) pathway including Tuberous sclerosis 2 (Tuberin)/ Ras homolog enriched in brain (RHEB2)/ FK506 binding protein 12-rapamycin associated protein 1 (mTOR) pathway [18]

Cytokine receptor signal transduction is controlled by limitation of the magnitude and duration of the signal through negative regulation. The mechanisms by which Somatotropin signaling can be attenuated include tyrosine dephosphorylation of JAK2 and IRS-1 by phosphatases Protein tyrosine phosphatase, non-receptor type 6 (SHP-1) and SHP-2, and cleavage of GHR by ADAM metallopeptidase domain 17 (ADAM17) with subsequently GHR inactivation [14], [19], [20].

References:

  1. Hackett RH, Wang YD, Larner AC
    Mapping of the cytoplasmic domain of the human growth hormone receptor required for the activation of Jak2 and Stat proteins. The Journal of biological chemistry 1995 Sep 8;270(36):21326-30
  2. Carter-Su C, Smit LS
    Signaling via JAK tyrosine kinases: growth hormone receptor as a model system. Recent progress in hormone research 1998;53:61-82; discussion 82-3
  3. Zhu T, Goh EL, Graichen R, Ling L, Lobie PE
    Signal transduction via the growth hormone receptor. Cellular signalling 2001 Sep;13(9):599-616
  4. Herrington J, Carter-Su C
    Signaling pathways activated by the growth hormone receptor. Trends in endocrinology and metabolism: TEM 2001 Aug;12(6):252-7
  5. Campbell GS, Pang L, Miyasaka T, Saltiel AR, Carter-Su C
    Stimulation by growth hormone of MAP kinase activity in 3T3-F442A fibroblasts. The Journal of biological chemistry 1992 Mar 25;267(9):6074-80
  6. Winston LA, Bertics PJ
    Growth hormone stimulates the tyrosine phosphorylation of 42- and 45-kDa ERK-related proteins. The Journal of biological chemistry 1992 Mar 5;267(7):4747-51
  7. Zhu T, Lobie PE
    Janus kinase 2-dependent activation of p38 mitogen-activated protein kinase by growth hormone. Resultant transcriptional activation of ATF-2 and CHOP, cytoskeletal re-organization and mitogenesis. The Journal of biological chemistry 2000 Jan 21;275(3):2103-14
  8. Winston LA, Hunter T
    JAK2, Ras, and Raf are required for activation of extracellular signal-regulated kinase/mitogen-activated protein kinase by growth hormone. The Journal of biological chemistry 1995 Dec 29;270(52):30837-40
  9. Vanderkuur JA, Butch ER, Waters SB, Pessin JE, Guan KL, Carter-Su C
    Signaling molecules involved in coupling growth hormone receptor to mitogen-activated protein kinase activation. Endocrinology 1997 Oct;138(10):4301-7
  10. Hodge C, Liao J, Stofega M, Guan K, Carter-Su C, Schwartz J
    Growth hormone stimulates phosphorylation and activation of elk-1 and expression of c-fos, egr-1, and junB through activation of extracellular signal-regulated kinases 1 and 2. The Journal of biological chemistry 1998 Nov 20;273(47):31327-36
  11. Clarkson RW, Shang CA, Levitt LK, Howard T, Waters MJ
    Ternary complex factors Elk-1 and Sap-1a mediate growth hormone-induced transcription of egr-1 (early growth response factor-1) in 3T3-F442A preadipocytes. Molecular endocrinology (Baltimore, Md.) 1999 Apr;13(4):619-31
  12. Pandey P, Avraham S, Kumar S, Nakazawa A, Place A, Ghanem L, Rana A, Kumar V, Majumder PK, Avraham H, Davis RJ, Kharbanda S
    Activation of p38 mitogen-activated protein kinase by PYK2/related adhesion focal tyrosine kinase-dependent mechanism. The Journal of biological chemistry 1999 Apr 9;274(15):10140-4
  13. Piwien-Pilipuk G, Van Mater D, Ross SE, MacDougald OA, Schwartz J
    Growth hormone regulates phosphorylation and function of CCAAT/enhancer-binding protein beta by modulating Akt and glycogen synthase kinase-3. The Journal of biological chemistry 2001 Jun 1;276(22):19664-71
  14. Kim SO, Jiang J, Yi W, Feng GS, Frank SJ
    Involvement of the Src homology 2-containing tyrosine phosphatase SHP-2 in growth hormone signaling. The Journal of biological chemistry 1998 Jan 23;273(4):2344-54
  15. Argetsinger LS, Hsu GW, Myers MG Jr, Billestrup N, White MF, Carter-Su C
    Growth hormone, interferon-gamma, and leukemia inhibitory factor promoted tyrosyl phosphorylation of insulin receptor substrate-1. The Journal of biological chemistry 1995 Jun 16;270(24):14685-92
  16. Liang L, Jiang J, Frank SJ
    Insulin receptor substrate-1-mediated enhancement of growth hormone-induced mitogen-activated protein kinase activation. Endocrinology 2000 Sep;141(9):3328-36
  17. Cese?a TI, Cui TX, Piwien-Pilipuk G, Kaplani J, Calinescu AA, Huo JS, I?iguez-Lluhi JA, Kwok R, Schwartz J
    Multiple mechanisms of growth hormone-regulated gene transcription. Molecular genetics and metabolism 2007 Feb;90(2):126-33
  18. Sharp ZD, Bartke A
    Evidence for down-regulation of phosphoinositide 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR)-dependent translation regulatory signaling pathways in Ames dwarf mice. The journals of gerontology. Series A, Biological sciences and medical sciences 2005 Mar;60(3):293-300
  19. Stofega MR, Herrington J, Billestrup N, Carter-Su C
    Mutation of the SHP-2 binding site in growth hormone (GH) receptor prolongs GH-promoted tyrosyl phosphorylation of GH receptor, JAK2, and STAT5B. Molecular endocrinology (Baltimore, Md.) 2000 Sep;14(9):1338-50
  20. Wang X, He K, Gerhart M, Huang Y, Jiang J, Paxton RJ, Yang S, Lu C, Menon RK, Black RA, Baumann G, Frank SJ
    Metalloprotease-mediated GH receptor proteolysis and GHBP shedding. Determination of extracellular domain stem region cleavage site. The Journal of biological chemistry 2002 Dec 27;277(52):50510-9

  1. Hackett RH, Wang YD, Larner AC
    Mapping of the cytoplasmic domain of the human growth hormone receptor required for the activation of Jak2 and Stat proteins. The Journal of biological chemistry 1995 Sep 8;270(36):21326-30
  2. Carter-Su C, Smit LS
    Signaling via JAK tyrosine kinases: growth hormone receptor as a model system. Recent progress in hormone research 1998;53:61-82; discussion 82-3
  3. Zhu T, Goh EL, Graichen R, Ling L, Lobie PE
    Signal transduction via the growth hormone receptor. Cellular signalling 2001 Sep;13(9):599-616
  4. Herrington J, Carter-Su C
    Signaling pathways activated by the growth hormone receptor. Trends in endocrinology and metabolism: TEM 2001 Aug;12(6):252-7
  5. Campbell GS, Pang L, Miyasaka T, Saltiel AR, Carter-Su C
    Stimulation by growth hormone of MAP kinase activity in 3T3-F442A fibroblasts. The Journal of biological chemistry 1992 Mar 25;267(9):6074-80
  6. Winston LA, Bertics PJ
    Growth hormone stimulates the tyrosine phosphorylation of 42- and 45-kDa ERK-related proteins. The Journal of biological chemistry 1992 Mar 5;267(7):4747-51
  7. Zhu T, Lobie PE
    Janus kinase 2-dependent activation of p38 mitogen-activated protein kinase by growth hormone. Resultant transcriptional activation of ATF-2 and CHOP, cytoskeletal re-organization and mitogenesis. The Journal of biological chemistry 2000 Jan 21;275(3):2103-14
  8. Winston LA, Hunter T
    JAK2, Ras, and Raf are required for activation of extracellular signal-regulated kinase/mitogen-activated protein kinase by growth hormone. The Journal of biological chemistry 1995 Dec 29;270(52):30837-40
  9. Vanderkuur JA, Butch ER, Waters SB, Pessin JE, Guan KL, Carter-Su C
    Signaling molecules involved in coupling growth hormone receptor to mitogen-activated protein kinase activation. Endocrinology 1997 Oct;138(10):4301-7
  10. Hodge C, Liao J, Stofega M, Guan K, Carter-Su C, Schwartz J
    Growth hormone stimulates phosphorylation and activation of elk-1 and expression of c-fos, egr-1, and junB through activation of extracellular signal-regulated kinases 1 and 2. The Journal of biological chemistry 1998 Nov 20;273(47):31327-36
  11. Clarkson RW, Shang CA, Levitt LK, Howard T, Waters MJ
    Ternary complex factors Elk-1 and Sap-1a mediate growth hormone-induced transcription of egr-1 (early growth response factor-1) in 3T3-F442A preadipocytes. Molecular endocrinology (Baltimore, Md.) 1999 Apr;13(4):619-31
  12. Pandey P, Avraham S, Kumar S, Nakazawa A, Place A, Ghanem L, Rana A, Kumar V, Majumder PK, Avraham H, Davis RJ, Kharbanda S
    Activation of p38 mitogen-activated protein kinase by PYK2/related adhesion focal tyrosine kinase-dependent mechanism. The Journal of biological chemistry 1999 Apr 9;274(15):10140-4
  13. Piwien-Pilipuk G, Van Mater D, Ross SE, MacDougald OA, Schwartz J
    Growth hormone regulates phosphorylation and function of CCAAT/enhancer-binding protein beta by modulating Akt and glycogen synthase kinase-3. The Journal of biological chemistry 2001 Jun 1;276(22):19664-71
  14. Kim SO, Jiang J, Yi W, Feng GS, Frank SJ
    Involvement of the Src homology 2-containing tyrosine phosphatase SHP-2 in growth hormone signaling. The Journal of biological chemistry 1998 Jan 23;273(4):2344-54
  15. Argetsinger LS, Hsu GW, Myers MG Jr, Billestrup N, White MF, Carter-Su C
    Growth hormone, interferon-gamma, and leukemia inhibitory factor promoted tyrosyl phosphorylation of insulin receptor substrate-1. The Journal of biological chemistry 1995 Jun 16;270(24):14685-92
  16. Liang L, Jiang J, Frank SJ
    Insulin receptor substrate-1-mediated enhancement of growth hormone-induced mitogen-activated protein kinase activation. Endocrinology 2000 Sep;141(9):3328-36
  17. Cese?a TI, Cui TX, Piwien-Pilipuk G, Kaplani J, Calinescu AA, Huo JS, I?iguez-Lluhi JA, Kwok R, Schwartz J
    Multiple mechanisms of growth hormone-regulated gene transcription. Molecular genetics and metabolism 2007 Feb;90(2):126-33
  18. Sharp ZD, Bartke A
    Evidence for down-regulation of phosphoinositide 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR)-dependent translation regulatory signaling pathways in Ames dwarf mice. The journals of gerontology. Series A, Biological sciences and medical sciences 2005 Mar;60(3):293-300
  19. Stofega MR, Herrington J, Billestrup N, Carter-Su C
    Mutation of the SHP-2 binding site in growth hormone (GH) receptor prolongs GH-promoted tyrosyl phosphorylation of GH receptor, JAK2, and STAT5B. Molecular endocrinology (Baltimore, Md.) 2000 Sep;14(9):1338-50
  20. Wang X, He K, Gerhart M, Huang Y, Jiang J, Paxton RJ, Yang S, Lu C, Menon RK, Black RA, Baumann G, Frank SJ
    Metalloprotease-mediated GH receptor proteolysis and GHBP shedding. Determination of extracellular domain stem region cleavage site. The Journal of biological chemistry 2002 Dec 27;277(52):50510-9

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