Somatostatin Activates Ras and ERK1/2 Via a G Protein βγ-subunit-initiated Pathway in Thyroid Cells

Overview

Journal Mol Cell Biochem

Publisher Springer

Specialty Biochemistry

Date 2015 Oct 17

PMID 26472731

Citations 4

Authors

Francisco J Rodriguez-Alvarez

Eva Jimenez-Mora

Maria Caballero

Beatriz Gallego

Antonio Chiloeches

Ma Jose Toro

Affiliations

Soon will be listed here.

Abstract

Somatostatin (SST) is one of the main regulators of thyroid function. It acts by binding to its receptors, which lead to the dissociation of G proteins into Gαi and Gβγ subunits. However, much less is known about the function of Gβγ in thyroid cells. Here, we studied the role of SST and Gβγ dimers released upon SST stimulation on the Ras-ERK1/2 pathway in FTRL-5 thyroid cells. We demonstrate that SST activates Ras through Gi proteins, since SST-induced Ras activation is inhibited by pertussis toxin. Moreover, the specific sequestration of Gβγ dimers decreases Ras-GTP and phosphorylated ERK1/2 levels, and overexpression of Gβγ increases ERK1/2 phosphorylation induced by SST, indicating that Gβγ dimers released after SST treatment mediate activation of Ras and ERK1/2. On the other hand, SST treatment does not modify the expression of the thyroid differentiation marker sodium/iodide symporter (NIS) through ERK1/2 activation. However, SST increases AKT activation and the inhibition of the Src/PI3K/AKT pathway increases NIS levels in SST-treated cells. Thus, we conclude that, in thyroid cells, signalling from SST receptors to ERK1/2 involves a Gβγ-mediated signal acting on a Ras-dependent pathway. Moreover, we demonstrate that SST might regulates NIS expression through a Src/PI3K/AKT-dependent mechanism, but not through ERK1/2 signalling, showing the main role of this hormone in thyroid function.

Citing Articles

Optimized new Shengmai powder inhibits myocardial fibrosis in heart failure by regulating the rat sarcoma/rapidly accelerated fibrosarcoma/mitogen-activated protein kinase kinase/extracellular regulated protein kinases signaling pathway.

Zeyu Z, Zhuangzhuang J, Yuwei S, Xuan Z, Ci W, Shuai W J Tradit Chin Med. 2024; 44(3):448-457.

PMID: 38767628 PMC: 11077160. DOI: 10.19852/j.cnki.jtcm.20240402.004.

CircRNA circRREB1 promotes tumorigenesis and progression of breast cancer by activating Erk1/2 signaling through interacting with GNB4.

Chen H, Wang X, Cheng H, Deng Y, Chen J, Wang B Heliyon. 2024; 10(7):e28785.

PMID: 38617926 PMC: 11015410. DOI: 10.1016/j.heliyon.2024.e28785.

GNG2 acts as a tumor suppressor in breast cancer through stimulating MRAS signaling.

Zhao A, Li D, Mao X, Yang M, Deng W, Hu W Cell Death Dis. 2022; 13(3):260.

PMID: 35322009 PMC: 8943035. DOI: 10.1038/s41419-022-04690-3.

Evaluation of preclinical efficacy of everolimus and pasireotide in thyroid cancer cell lines and xenograft models.

Owonikoko T, Zhang G, Lallani S, Chen Z, Martinson D, Khuri F PLoS One. 2019; 14(2):e0206309.

PMID: 30807575 PMC: 6390992. DOI: 10.1371/journal.pone.0206309.

References

Crespo P, Xu N, Simonds W, Gutkind J . Ras-dependent activation of MAP kinase pathway mediated by G-protein beta gamma subunits. Nature. 1994; 369(6479):418-20. DOI: 10.1038/369418a0. View

Hwang J, Choi S, Fraser I, Chang M, Simon M . Silencing the expression of multiple Gbeta-subunits eliminates signaling mediated by all four families of G proteins. Proc Natl Acad Sci U S A. 2005; 102(27):9493-8. PMC: 1172260. DOI: 10.1073/pnas.0503503102. View

de Rooij J, Bos J . Minimal Ras-binding domain of Raf1 can be used as an activation-specific probe for Ras. Oncogene. 1997; 14(5):623-5. DOI: 10.1038/sj.onc.1201005. View

Xing M . BRAF mutation in papillary thyroid cancer: pathogenic role, molecular bases, and clinical implications. Endocr Rev. 2007; 28(7):742-62. DOI: 10.1210/er.2007-0007. View

Zaballos M, Garcia B, Santisteban P . Gbetagamma dimers released in response to thyrotropin activate phosphoinositide 3-kinase and regulate gene expression in thyroid cells. Mol Endocrinol. 2008; 22(5):1183-99. PMC: 5419518. DOI: 10.1210/me.2007-0093. View

Florio T, Yao H, Carey K, Dillon T, Stork P . Somatostatin activation of mitogen-activated protein kinase via somatostatin receptor 1 (SSTR1). Mol Endocrinol. 1999; 13(1):24-37. DOI: 10.1210/mend.13.1.0224. View

Liu Y, Zhang X, Ringel M, Jhiang S . Modulation of sodium iodide symporter expression and function by LY294002, Akti-1/2 and Rapamycin in thyroid cells. Endocr Relat Cancer. 2012; 19(3):291-304. PMC: 3736852. DOI: 10.1530/ERC-11-0288. View

Garcia B, Santisteban P . PI3K is involved in the IGF-I inhibition of TSH-induced sodium/iodide symporter gene expression. Mol Endocrinol. 2002; 16(2):342-52. DOI: 10.1210/mend.16.2.0774. View

Iacovelli L, Capobianco L, Salvatore L, Sallese M, DAncona G, De Blasi A . Thyrotropin activates mitogen-activated protein kinase pathway in FRTL-5 by a cAMP-dependent protein kinase A-independent mechanism. Mol Pharmacol. 2001; 60(5):924-33. DOI: 10.1124/mol.60.5.924. View

10.

Vidal M, Wieland T, Lohse M, Lorenz K . β-Adrenergic receptor stimulation causes cardiac hypertrophy via a Gβγ/Erk-dependent pathway. Cardiovasc Res. 2012; 96(2):255-64. DOI: 10.1093/cvr/cvs249. View

11.

Koch W, Hawes B, Allen L, Lefkowitz R . Direct evidence that Gi-coupled receptor stimulation of mitogen-activated protein kinase is mediated by G beta gamma activation of p21ras. Proc Natl Acad Sci U S A. 1994; 91(26):12706-10. PMC: 45508. DOI: 10.1073/pnas.91.26.12706. View

12.

Riesco-Eizaguirre G, Gutierrez-Martinez P, Garcia-Cabezas M, Nistal M, Santisteban P . The oncogene BRAF V600E is associated with a high risk of recurrence and less differentiated papillary thyroid carcinoma due to the impairment of Na+/I- targeting to the membrane. Endocr Relat Cancer. 2006; 13(1):257-69. DOI: 10.1677/erc.1.01119. View

13.

Guan J, Luo Y, Denker B . Purkinje cell protein-2 (Pcp2) stimulates differentiation in PC12 cells by Gbetagamma-mediated activation of Ras and p38 MAPK. Biochem J. 2005; 392(Pt 2):389-97. PMC: 1316275. DOI: 10.1042/BJ20042102. View

14.

Medina D, Velasco J, Santisteban P . Somatostatin is expressed in FRTL-5 thyroid cells and prevents thyrotropin-mediated down-regulation of the cyclin-dependent kinase inhibitor p27kip1. Endocrinology. 1999; 140(1):87-95. DOI: 10.1210/endo.140.1.6426. View

15.

Ciullo I, Di Domenico M, Migliaccio A, Avvedimento E . cAMP signaling selectively influences Ras effectors pathways. Oncogene. 2001; 20(10):1186-92. DOI: 10.1038/sj.onc.1204219. View

16.

Obara Y, Okano Y, Ono S, Yamauchi A, Hoshino T, Kurose H . Betagamma subunits of G(i/o) suppress EGF-induced ERK5 phosphorylation, whereas ERK1/2 phosphorylation is enhanced. Cell Signal. 2008; 20(7):1275-83. DOI: 10.1016/j.cellsig.2008.02.016. View

17.

Avidor-Reiss T, Nevo I, Levy R, Pfeuffer T, Vogel Z . Chronic opioid treatment induces adenylyl cyclase V superactivation. Involvement of Gbetagamma. J Biol Chem. 1996; 271(35):21309-15. DOI: 10.1074/jbc.271.35.21309. View

18.

Medina D, Toro M, Santisteban P . Somatostatin interferes with thyrotropin-induced G1-S transition mediated by cAMP-dependent protein kinase and phosphatidylinositol 3-kinase. Involvement of RhoA and cyclin E x cyclin-dependent kinase 2 complexes. J Biol Chem. 2000; 275(20):15549-56. DOI: 10.1074/jbc.275.20.15549. View

19.

Craddock B, Hobbs J, Edmead C, Welham M . Phosphoinositide 3-kinase-dependent regulation of interleukin-3-induced proliferation: involvement of mitogen-activated protein kinases, SHP2 and Gab2. J Biol Chem. 2001; 276(26):24274-83. DOI: 10.1074/jbc.M009098200. View

20.

Lahlou H, Saint-Laurent N, Esteve J, Eychene A, Pradayrol L, Pyronnet S . sst2 Somatostatin receptor inhibits cell proliferation through Ras-, Rap1-, and B-Raf-dependent ERK2 activation. J Biol Chem. 2003; 278(41):39356-71. DOI: 10.1074/jbc.M304524200. View