TYK2-induced Phosphorylation of Y640 Suppresses STAT3 Transcriptional Activity

Overview

Journal Sci Rep

Specialty Science

Date 2017 Nov 23

PMID 29162862

Citations 8

Authors

Raffaele Mori

Joris Wauman

Laura Icardi

Jose Van der Heyden

Lode De Cauwer

Frank Peelman

Karolien De Bosscher

Jan Tavernier

Affiliations

Soon will be listed here.

Abstract

STAT3 is a pleiotropic transcription factor involved in homeostatic and host defense processes in the human body. It is activated by numerous cytokines and growth factors and generates a series of cellular effects. Of the STAT-mediated signal transduction pathways, STAT3 transcriptional control is best understood. Jak kinase dependent activation of STAT3 relies on Y705 phosphorylation triggering a conformational switch that is stabilized by intermolecular interactions between SH2 domains and the pY705 motif. We here show that a second tyrosine phosphorylation within the SH2 domain at position Y640, induced by Tyk2, negatively controls STAT3 activity. The Y640F mutation leads to stabilization of activated STAT3 homodimers, accelerated nuclear translocation and superior transcriptional activity following IL-6 and LIF stimulation. Moreover, it unlocks type I IFN-dependent STAT3 signalling in cells that are normally refractory to STAT3 transcriptional activation.

Citing Articles

Cell-type-specific requirement for TYK2 in murine immune cells under steady state and challenged conditions.

Karjalainen A, Witalisz-Siepracka A, Prchal-Murphy M, Martin D, Sternberg F, Krunic M Cell Mol Life Sci. 2025; 82(1):98.

PMID: 40025196 PMC: 11872851. DOI: 10.1007/s00018-025-05625-9.

Association between Cardiovascular Response and Inflammatory Cytokines in Non-Small Cell Lung Cancer Patients.

Wang X, Cao M, Liu Z, Chen L, Zhou Y, Gao P J Cardiovasc Dev Dis. 2023; 10(4).

PMID: 37103052 PMC: 10144044. DOI: 10.3390/jcdd10040173.

CD200R1 promotes interleukin-17 production by group 3 innate lymphoid cells by enhancing signal transducer and activator of transcription 3 activation.

Linley H, Ogden A, Jaigirdar S, Buckingham L, Cox J, Priestley M Mucosal Immunol. 2023; 16(2):167-179.

PMID: 36623588 PMC: 10270648. DOI: 10.1016/j.mucimm.2023.01.001.

Frequent somatic mosaicism in T lymphocyte subsets in individuals with and without multiple sclerosis.

Van Horebeek L, Dedoncker N, Dubois B, Goris A Front Immunol. 2023; 13:993178.

PMID: 36618380 PMC: 9817019. DOI: 10.3389/fimmu.2022.993178.

Tyrosine Phosphorylation Profiling Revealed the Signaling Network Characteristics of CAMKK2 in Gastric Adenocarcinoma.

Najar M, Arefian M, Sidransky D, Gowda H, Keshava Prasad T, Modi P Front Genet. 2022; 13:854764.

PMID: 35646067 PMC: 9136244. DOI: 10.3389/fgene.2022.854764.

References

Hirano T, Ishihara K, Hibi M . Roles of STAT3 in mediating the cell growth, differentiation and survival signals relayed through the IL-6 family of cytokine receptors. Oncogene. 2000; 19(21):2548-56. DOI: 10.1038/sj.onc.1203551. View

Bowman T, Garcia R, Turkson J, Jove R . STATs in oncogenesis. Oncogene. 2000; 19(21):2474-88. DOI: 10.1038/sj.onc.1203527. View

Ray S, Zhao Y, Jamaluddin M, Edeh C, Lee C, Brasier A . Inducible STAT3 NH2 terminal mono-ubiquitination promotes BRD4 complex formation to regulate apoptosis. Cell Signal. 2014; 26(7):1445-55. PMC: 4067092. DOI: 10.1016/j.cellsig.2014.03.007. View

Radtke S, Hermanns H, Haan C, Schmitz-Van de Leur H, Gascan H, Heinrich P . Novel role of Janus kinase 1 in the regulation of oncostatin M receptor surface expression. J Biol Chem. 2002; 277(13):11297-305. DOI: 10.1074/jbc.M100822200. View

Nie Y, Erion D, Yuan Z, Dietrich M, Shulman G, Horvath T . STAT3 inhibition of gluconeogenesis is downregulated by SirT1. Nat Cell Biol. 2009; 11(4):492-500. PMC: 2790597. DOI: 10.1038/ncb1857. View

Rane S, Reddy E . JAKs, STATs and Src kinases in hematopoiesis. Oncogene. 2002; 21(21):3334-58. DOI: 10.1038/sj.onc.1205398. View

Icardi L, Mori R, Gesellchen V, Eyckerman S, De Cauwer L, Verhelst J . The Sin3a repressor complex is a master regulator of STAT transcriptional activity. Proc Natl Acad Sci U S A. 2012; 109(30):12058-63. PMC: 3409767. DOI: 10.1073/pnas.1206458109. View

Kim L, Song L, Haura E . Src kinases as therapeutic targets for cancer. Nat Rev Clin Oncol. 2009; 6(10):587-95. DOI: 10.1038/nrclinonc.2009.129. View

Krieger E, Joo K, Lee J, Lee J, Raman S, Thompson J . Improving physical realism, stereochemistry, and side-chain accuracy in homology modeling: Four approaches that performed well in CASP8. Proteins. 2009; 77 Suppl 9:114-22. PMC: 2922016. DOI: 10.1002/prot.22570. View

10.

Sohn S, Barrett K, Van Abbema A, Chang C, Kohli P, Kanda H . A restricted role for TYK2 catalytic activity in human cytokine responses revealed by novel TYK2-selective inhibitors. J Immunol. 2013; 191(5):2205-16. PMC: 3748334. DOI: 10.4049/jimmunol.1202859. View

11.

Constantinescu S, Girardot M, Pecquet C . Mining for JAK-STAT mutations in cancer. Trends Biochem Sci. 2008; 33(3):122-31. DOI: 10.1016/j.tibs.2007.12.002. View

12.

Graham F, Van Der Eb A . A new technique for the assay of infectivity of human adenovirus 5 DNA. Virology. 1973; 52(2):456-67. DOI: 10.1016/0042-6822(73)90341-3. View

13.

Jerez A, Clemente M, Makishima H, Koskela H, LeBlanc F, Ng K . STAT3 mutations unify the pathogenesis of chronic lymphoproliferative disorders of NK cells and T-cell large granular lymphocyte leukemia. Blood. 2012; 120(15):3048-57. PMC: 3471515. DOI: 10.1182/blood-2012-06-435297. View

14.

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

15.

Zhou Z, Wang M, Li J, Xiao M, Chin Y, Cheng J . SUMOylation and SENP3 regulate STAT3 activation in head and neck cancer. Oncogene. 2016; 35(45):5826-5838. PMC: 5116054. DOI: 10.1038/onc.2016.124. View

16.

Zhong Z, Wen Z, Darnell Jr J . Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science. 1994; 264(5155):95-8. DOI: 10.1126/science.8140422. View

17.

Mali S . Review of STAT3 (Signal Transducers and Activators of Transcription) in head and neck cancer. Oral Oncol. 2015; 51(6):565-9. DOI: 10.1016/j.oraloncology.2015.03.004. View

18.

Kretzschmar A, Dinger M, Henze C, Brocke-Heidrich K, Horn F . Analysis of Stat3 (signal transducer and activator of transcription 3) dimerization by fluorescence resonance energy transfer in living cells. Biochem J. 2003; 377(Pt 2):289-97. PMC: 1223859. DOI: 10.1042/BJ20030708. View

19.

Guschin D, Rogers N, Briscoe J, Witthuhn B, Watling D, Horn F . A major role for the protein tyrosine kinase JAK1 in the JAK/STAT signal transduction pathway in response to interleukin-6. EMBO J. 1995; 14(7):1421-9. PMC: 398228. DOI: 10.1002/j.1460-2075.1995.tb07128.x. View

20.

Reich N . STATs get their move on. JAKSTAT. 2014; 2(4):e27080. PMC: 3891633. DOI: 10.4161/jkst.27080. View