Post-Receptor Inhibitors of the GHR-JAK2-STAT Pathway in the Growth Hormone Signal Transduction

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2018 Jun 23

PMID 29932147

Citations 14

Authors

Maciej Wojcik

Agata Krawczynska

Hanna Antushevich

Andrzej Przemyslaw Herman

Affiliations

Soon will be listed here.

Abstract

The growth hormone (GH) plays a key role in the regulation of metabolic processes in an organism. Determination of the correct structure and functioning of the growth hormone receptor (GHR) allowed for a more detailed research of its post-receptor regulators, which substantially influences its signal transduction. This review is focused on the description of the post-receptor inhibitors of the GHR-JAK2-STAT pathway, which is one of the most important pathways in the transduction of the somatotropic axis signal. The aim of this review is the short characterization of the main post-receptor inhibitors, such as: cytokine-inducible SH2-containing protein (CIS), Suppressors of Cytokine Signaling (SOCS) 1, 2 and 3, sirtuin 1 (SIRT1), protein inhibitors of activated STAT (PIAS) 1, 3 and PIAS4, protein tyrosine phosphatases (PTP) 1B and H1, Src homology 2 (SH2) domain containing protein tyrosine phosphatase (SHP) 1, 2 and signal regulatory protein (SIRP) α1. The equilibrium between these regulators activity and inhibition is of special concern because, as many studies showed, even slight imbalance may disrupt the GH activity causing serious diseases. The regulation of the described inhibitors expression and activity may be a point of interest for pharmaceutical industry.

Citing Articles

SOCS2 inhibits the tumorigenesis of GISTs and increases the sensitivity of GISTs to imatinib by suppression of KIT activation.

Zhang L, Xiao K, Zhang S, Zhao S, Liu Z, Wang M Sci Rep. 2025; 15(1):4779.

PMID: 39922931 PMC: 11807132. DOI: 10.1038/s41598-025-89477-0.

Growth hormone signaling and clinical implications: from molecular to therapeutic perspectives.

Aghili Z, Khoshnevisan G, Mostoli R, Alibaglouei M, Zarkesh-Esfahani S Mol Biol Rep. 2025; 52(1):202.

PMID: 39904816 DOI: 10.1007/s11033-025-10304-w.

The Aggravating Role of Failing Neuropeptide Networks in the Development of Sporadic Alzheimer's Disease.

Jaszberenyi M, Thurzo B, Jayakumar A, Schally A Int J Mol Sci. 2024; 25(23).

PMID: 39684795 PMC: 11641508. DOI: 10.3390/ijms252313086.

The Effect of Endotoxin-Induced Inflammation on the Activity of the Somatotropic Axis in Sheep.

Wojcik M, Zieba D, Bochenek J, Krawczynska A, Barszcz M, Gajewska A Int J Inflam. 2024; 2024:1057299.

PMID: 39149693 PMC: 11325012. DOI: 10.1155/2024/1057299.

Relationship between Serum Sirtuin 1 and Growth Hormone/Insulin-like Growth Factor 1 Concentrations in Children with Growth Hormone Deficiency and Idiopathic Short Stature.

Fedorczak A, Kowalik D, Kopciuch J, Glowacka E, Mikolajczyk K, Tkaczyk M Biomedicines. 2024; 12(7).

PMID: 39062007 PMC: 11274889. DOI: 10.3390/biomedicines12071433.

References

Cui Y, Riedlinger G, Miyoshi K, Tang W, Li C, Deng C . Inactivation of Stat5 in mouse mammary epithelium during pregnancy reveals distinct functions in cell proliferation, survival, and differentiation. Mol Cell Biol. 2004; 24(18):8037-47. PMC: 515028. DOI: 10.1128/MCB.24.18.8037-8047.2004. View

Greenhalgh C, Rico-Bautista E, Lorentzon M, Thaus A, Morgan P, Willson T . SOCS2 negatively regulates growth hormone action in vitro and in vivo. J Clin Invest. 2005; 115(2):397-406. PMC: 546423. DOI: 10.1172/JCI22710. View

Peltola K, Paukku K, Aho T, Ruuska M, Silvennoinen O, Koskinen P . Pim-1 kinase inhibits STAT5-dependent transcription via its interactions with SOCS1 and SOCS3. Blood. 2004; 103(10):3744-50. DOI: 10.1182/blood-2003-09-3126. View

Watanobe H, Habu S . Leptin regulates growth hormone-releasing factor, somatostatin, and alpha-melanocyte-stimulating hormone but not neuropeptide Y release in rat hypothalamus in vivo: relation with growth hormone secretion. J Neurosci. 2002; 22(14):6265-71. PMC: 6757925. DOI: 20026615. View

Marin T, Keith K, Davies B, Conner D, Guha P, Kalaitzidis D . Rapamycin reverses hypertrophic cardiomyopathy in a mouse model of LEOPARD syndrome-associated PTPN11 mutation. J Clin Invest. 2011; 121(3):1026-43. PMC: 3049377. DOI: 10.1172/JCI44972. View

Metcalf D, Greenhalgh C, Viney E, Willson T, Starr R, Nicola N . Gigantism in mice lacking suppressor of cytokine signalling-2. Nature. 2000; 405(6790):1069-73. DOI: 10.1038/35016611. View

Neel B, Tonks N . Protein tyrosine phosphatases in signal transduction. Curr Opin Cell Biol. 1997; 9(2):193-204. DOI: 10.1016/s0955-0674(97)80063-4. View

Ceranowicz P, Warzecha Z, Dembinski A . Peptidyl hormones of endocrine cells origin in the gut--their discovery and physiological relevance. J Physiol Pharmacol. 2015; 66(1):11-27. View

Beuvink I, Hess D, Flotow H, Hofsteenge J, Groner B, Hynes N . Stat5a serine phosphorylation. Serine 779 is constitutively phosphorylated in the mammary gland, and serine 725 phosphorylation influences prolactin-stimulated in vitro DNA binding activity. J Biol Chem. 2000; 275(14):10247-55. DOI: 10.1074/jbc.275.14.10247. View

10.

Liu B, Mink S, Wong K, Stein N, Getman C, Dempsey P . PIAS1 selectively inhibits interferon-inducible genes and is important in innate immunity. Nat Immunol. 2004; 5(9):891-8. DOI: 10.1038/ni1104. View

11.

Wen Z, Zhong Z, Darnell Jr J . Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation. Cell. 1995; 82(2):241-50. DOI: 10.1016/0092-8674(95)90311-9. View

12.

Gu F, Dube N, Kim J, Cheng A, Ibarra-Sanchez M, Tremblay M . Protein tyrosine phosphatase 1B attenuates growth hormone-mediated JAK2-STAT signaling. Mol Cell Biol. 2003; 23(11):3753-62. PMC: 155228. DOI: 10.1128/MCB.23.11.3753-3762.2003. View

13.

Yao-Xia L, Jing-Yan C, Xia-Lian T, Ping C, Min Z . The 20kDa and 22kDa forms of human growth hormone (hGH) exhibit different intracellular signalling profiles and properties. Gen Comp Endocrinol. 2017; 248:49-54. DOI: 10.1016/j.ygcen.2017.04.010. View

14.

Warzecha Z, Dembinski A, Ceranowicz P, Konturek S, Tomaszewska R, Stachura J . IGF-1 stimulates production of interleukin-10 and inhibits development of caerulein-induced pancreatitis. J Physiol Pharmacol. 2004; 54(4):575-90. View

15.

Gouilleux F, Wakao H, Mundt M, Groner B . Prolactin induces phosphorylation of Tyr694 of Stat5 (MGF), a prerequisite for DNA binding and induction of transcription. EMBO J. 1994; 13(18):4361-9. PMC: 395363. DOI: 10.1002/j.1460-2075.1994.tb06756.x. View

16.

Irandoust M, Aarts L, Roovers O, Gits J, Erkeland S, Touw I . Suppressor of cytokine signaling 3 controls lysosomal routing of G-CSF receptor. EMBO J. 2007; 26(7):1782-93. PMC: 1847666. DOI: 10.1038/sj.emboj.7601640. View

17.

Vidal O, Merino R, Rico-Bautista E, Fernandez-Perez L, Chia D, Woelfle J . In vivo transcript profiling and phylogenetic analysis identifies suppressor of cytokine signaling 2 as a direct signal transducer and activator of transcription 5b target in liver. Mol Endocrinol. 2006; 21(1):293-311. DOI: 10.1210/me.2006-0096. View

18.

Ram P, Waxman D . Role of the cytokine-inducible SH2 protein CIS in desensitization of STAT5b signaling by continuous growth hormone. J Biol Chem. 2000; 275(50):39487-96. DOI: 10.1074/jbc.M004755200. View

19.

Pelosi L, Giacinti C, Nardis C, Borsellino G, Rizzuto E, Nicoletti C . Local expression of IGF-1 accelerates muscle regeneration by rapidly modulating inflammatory cytokines and chemokines. FASEB J. 2007; 21(7):1393-402. DOI: 10.1096/fj.06-7690com. View

20.

Yang J, Liu L, He D, Song X, Liang X, Zhao Z . Crystal structure of human protein-tyrosine phosphatase SHP-1. J Biol Chem. 2002; 278(8):6516-20. DOI: 10.1074/jbc.M210430200. View