Development - Growth hormone signaling via STATs and PLC/IP3

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Growth hormone signaling via STATs and PLC/IP3

Growth hormone (GH or Somatotropin) is a major growth-promoting and metabolic regulatory hormone. Interaction of GH with its cell surface receptor (GHR) causes receptor dimerization and activation of the GHR-associated cytoplasmic tyrosine kinase, Janus kinase 2 (JAK2) [1], [2], [3].

The signal transducers and activators of transcription (STATs) family of transcription factors are key molecules in the GH signaling process. GH-activated JAK2 phosphorylates at least four members of this family (STAT1, STAT3, STAT5A and STAT5B), leading to their dimerization, nuclear localization, DNA binding and activation of transcription [4]. STAT5A and STAT5B are the predominant STATs utilized by GH [5].

GH stimulates activation of at least two tyrosine kinases, v-Src sarcoma viral oncogene homolog (c-Src) and FYN oncogene related to SRC, FGR, YES (Fyn) [6], both of which exist as components of a multiprotein signaling complex centered on an adapter protein v-Crk sarcoma virus CT10 oncogene homolog (Crk) and Crk-associated substrate Breast cancer anti-estrogen resistance 1 (p130Cas).

GH also activates PTK2 protein tyrosine kinase 2 (FAK1) via its phosphorylation by JAK2. This activation results in tyrosine phosphorylation of the two FAK1-associated substrates, namely, Paxillin and Tensin [7]. GH stimulates the reorganization of the actin cytoskeleton in cells with fibroblastic morphology [8].

Moreover GH signaling can activate Mitogen-activated protein kinase 8 (JNK1) via formation of multiprotein complex encompassing FAK1-associated Crk and Rap guanine nucleotide exchange factor 1 (C3G) [9]. Crk directly binds and activates JNK1 [10]. JNK1 then phosphorylates Jun oncogene (c-Jun) and activates its transcriptional activity [11].

GH also activates RAS-related protein-1 (Rap1) via Crk-p130Cas assembly. Rap1 controls cell invasion and survival [9].

GH exerts many of its physiological functions by regulating the transcription of genes for a variety of proteins, including Insulin-like growth factor-1 (IGF-1), Fibrinogen beta and transcription factors such as Interferon regulatory factor 1 (IRF1) and v-Fos FBJ murine osteosarcoma viral oncogene homolog (c-Fos). These target genes are regulated via STAT transcription factors [12], [13], [14], [15], [16].

Phospholipase C gamma (PLC-gamma) is tyrosine phosphorylated via its direct binding to the JAK2/GHR complexes. PLC-gamma catalyzes the production of the second messenger metabolites, diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3), leading to intracellular Ca(II) mobilization and protein kinase C activation (such as PKC-delta) [17], [18], [19].

Moreover it has been recently found that PLC-gamma 1 is also involved in negative regulation of GHR signaling via direct binding to JAK2. This binding lead to the activation of PLC-gamma 1 and, via a feedback mechanism, PLC-gamma 1 can inhibit JAK2 activity by recruiting Protein tyrosine phosphatase, non-receptor type 1 (PTP-1B) [20].

The mechanisms by which GH signaling can be attenuated also employ suppressors of cytokine signaling (SOCS) protein family such as SOCS1, SOCS2 and SOCS3. The latter proteins play important roles in regulating GH-regulated processes [21]. The transmembrane metalloproteinase ADAM17 can cleave and inactivate GHR [22].

References:

  1. 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
  2. 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
  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, Smit LS, Schwartz J, Carter-Su C
    The role of STAT proteins in growth hormone signaling. Oncogene 2000 May 15;19(21):2585-97
  5. Teglund S, McKay C, Schuetz E, van Deursen JM, Stravopodis D, Wang D, Brown M, Bodner S, Grosveld G, Ihle JN
    Stat5a and Stat5b proteins have essential and nonessential, or redundant, roles in cytokine responses. Cell 1998 May 29;93(5):841-50
  6. Zhu T, Goh EL, LeRoith D, Lobie PE
    Growth hormone stimulates the formation of a multiprotein signaling complex involving p130(Cas) and CrkII. Resultant activation of c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK). The Journal of biological chemistry 1998 Dec 11;273(50):33864-75
  7. Zhu T, Goh EL, Lobie PE
    Growth hormone stimulates the tyrosine phosphorylation and association of p125 focal adhesion kinase (FAK) with JAK2. Fak is not required for stat-mediated transcription. The Journal of biological chemistry 1998 Apr 24;273(17):10682-9
  8. Goh EL, Pircher TJ, Wood TJ, Norstedt G, Graichen R, Lobie PE
    Growth hormone-induced reorganization of the actin cytoskeleton is not required for STAT5 (signal transducer and activator of transcription-5)-mediated transcription. Endocrinology 1997 Aug;138(8):3207-15
  9. Ling L, Zhu T, Lobie PE
    Src-CrkII-C3G-dependent activation of Rap1 switches growth hormone-stimulated p44/42 MAP kinase and JNK/SAPK activities. The Journal of biological chemistry 2003 Jul 18;278(29):27301-11
  10. Girardin SE, Yaniv M
    A direct interaction between JNK1 and CrkII is critical for Rac1-induced JNK activation. The EMBO journal 2001 Jul 2;20(13):3437-46
  11. Davis RJ
    Signal transduction by the JNK group of MAP kinases. Cell 2000 Oct 13;103(2):239-52
  12. Le Stunff C, Rotwein P
    Growth hormone stimulates interferon regulatory factor-1 gene expression in the liver. Endocrinology 1998 Mar;139(3):859-66
  13. Thompson BJ, Shang CA, Waters MJ
    Identification of genes induced by growth hormone in rat liver using cDNA arrays. Endocrinology 2000 Nov;141(11):4321-4
  14. Woelfle J, Rotwein P
    In vivo regulation of growth hormone-stimulated gene transcription by STAT5b. American journal of physiology. Endocrinology and metabolism 2004 Mar;286(3):E393-401
  15. Wang Y, Jiang H
    Identification of a distal STAT5-binding DNA region that may mediate growth hormone regulation of insulin-like growth factor-I gene expression. The Journal of biological chemistry 2005 Mar 25;280(12):10955-63
  16. Chia DJ, Ono M, Woelfle J, Schlesinger-Massart M, Jiang H, Rotwein P
    Characterization of distinct Stat5b binding sites that mediate growth hormone-stimulated IGF-I gene transcription. The Journal of biological chemistry 2006 Feb 10;281(6):3190-7
  17. Towns R, Kostyo JL, Martin D, Chou SY, Bennink MR
    The stimulatory effect of insulin on diacylglycerol generation in adipocyte membranes from ob/ob mice is impaired by growth hormone. Endocrinology 1993 Apr;132(4):1671-6
  18. MacKenzie S, Fleming I, Houslay MD, Anderson NG, Kilgour E
    Growth hormone and phorbol esters require specific protein kinase C isoforms to activate mitogen-activated protein kinases in 3T3-F442A cells. The Biochemical journal 1997 May 15;324 ( Pt 1):159-65
  19. Marrero I, Déniz A
    The phospholipase C-InsP3 pathway is involved in calcium mobilization induced by growth hormone in hepatocytes. Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society 2004 Apr;14(2):85-90
  20. Choi JH, Kim HS, Kim SH, Yang YR, Bae YS, Chang JS, Kwon HM, Ryu SH, Suh PG
    Phospholipase Cgamma1 negatively regulates growth hormone signalling by forming a ternary complex with Jak2 and protein tyrosine phosphatase-1B. Nature cell biology 2006 Dec;8(12):1389-97
  21. Flores-Morales A, Greenhalgh CJ, Norstedt G, Rico-Bautista E
    Negative regulation of growth hormone receptor signaling. Molecular endocrinology (Baltimore, Md.) 2006 Feb;20(2):241-53
  22. 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. 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
  2. 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
  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, Smit LS, Schwartz J, Carter-Su C
    The role of STAT proteins in growth hormone signaling. Oncogene 2000 May 15;19(21):2585-97
  5. Teglund S, McKay C, Schuetz E, van Deursen JM, Stravopodis D, Wang D, Brown M, Bodner S, Grosveld G, Ihle JN
    Stat5a and Stat5b proteins have essential and nonessential, or redundant, roles in cytokine responses. Cell 1998 May 29;93(5):841-50
  6. Zhu T, Goh EL, LeRoith D, Lobie PE
    Growth hormone stimulates the formation of a multiprotein signaling complex involving p130(Cas) and CrkII. Resultant activation of c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK). The Journal of biological chemistry 1998 Dec 11;273(50):33864-75
  7. Zhu T, Goh EL, Lobie PE
    Growth hormone stimulates the tyrosine phosphorylation and association of p125 focal adhesion kinase (FAK) with JAK2. Fak is not required for stat-mediated transcription. The Journal of biological chemistry 1998 Apr 24;273(17):10682-9
  8. Goh EL, Pircher TJ, Wood TJ, Norstedt G, Graichen R, Lobie PE
    Growth hormone-induced reorganization of the actin cytoskeleton is not required for STAT5 (signal transducer and activator of transcription-5)-mediated transcription. Endocrinology 1997 Aug;138(8):3207-15
  9. Ling L, Zhu T, Lobie PE
    Src-CrkII-C3G-dependent activation of Rap1 switches growth hormone-stimulated p44/42 MAP kinase and JNK/SAPK activities. The Journal of biological chemistry 2003 Jul 18;278(29):27301-11
  10. Girardin SE, Yaniv M
    A direct interaction between JNK1 and CrkII is critical for Rac1-induced JNK activation. The EMBO journal 2001 Jul 2;20(13):3437-46
  11. Davis RJ
    Signal transduction by the JNK group of MAP kinases. Cell 2000 Oct 13;103(2):239-52
  12. Le Stunff C, Rotwein P
    Growth hormone stimulates interferon regulatory factor-1 gene expression in the liver. Endocrinology 1998 Mar;139(3):859-66
  13. Thompson BJ, Shang CA, Waters MJ
    Identification of genes induced by growth hormone in rat liver using cDNA arrays. Endocrinology 2000 Nov;141(11):4321-4
  14. Woelfle J, Rotwein P
    In vivo regulation of growth hormone-stimulated gene transcription by STAT5b. American journal of physiology. Endocrinology and metabolism 2004 Mar;286(3):E393-401
  15. Wang Y, Jiang H
    Identification of a distal STAT5-binding DNA region that may mediate growth hormone regulation of insulin-like growth factor-I gene expression. The Journal of biological chemistry 2005 Mar 25;280(12):10955-63
  16. Chia DJ, Ono M, Woelfle J, Schlesinger-Massart M, Jiang H, Rotwein P
    Characterization of distinct Stat5b binding sites that mediate growth hormone-stimulated IGF-I gene transcription. The Journal of biological chemistry 2006 Feb 10;281(6):3190-7
  17. Towns R, Kostyo JL, Martin D, Chou SY, Bennink MR
    The stimulatory effect of insulin on diacylglycerol generation in adipocyte membranes from ob/ob mice is impaired by growth hormone. Endocrinology 1993 Apr;132(4):1671-6
  18. MacKenzie S, Fleming I, Houslay MD, Anderson NG, Kilgour E
    Growth hormone and phorbol esters require specific protein kinase C isoforms to activate mitogen-activated protein kinases in 3T3-F442A cells. The Biochemical journal 1997 May 15;324 ( Pt 1):159-65
  19. Marrero I, Déniz A
    The phospholipase C-InsP3 pathway is involved in calcium mobilization induced by growth hormone in hepatocytes. Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society 2004 Apr;14(2):85-90
  20. Choi JH, Kim HS, Kim SH, Yang YR, Bae YS, Chang JS, Kwon HM, Ryu SH, Suh PG
    Phospholipase Cgamma1 negatively regulates growth hormone signalling by forming a ternary complex with Jak2 and protein tyrosine phosphatase-1B. Nature cell biology 2006 Dec;8(12):1389-97
  21. Flores-Morales A, Greenhalgh CJ, Norstedt G, Rico-Bautista E
    Negative regulation of growth hormone receptor signaling. Molecular endocrinology (Baltimore, Md.) 2006 Feb;20(2):241-53
  22. 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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