title: Reciprocal regulation of C-Maf tyrosine phosphorylation by Tec and Ptpn22.
abstract: C-Maf plays an important role in regulating cytokine production in TH cells. Its transactivation of IL-4 is optimized by phosphorylation at Tyr21, Tyr92, and Tyr131. However, the molecular mechanism regulating its tyrosine phosphorylation remains unknown. In this study, we demonstrate that Tec kinase family member Tec, but not Rlk or Itk, is a tyrosine kinase of c-Maf and that Tec enhances c-Maf-dependent IL-4 promoter activity. This effect of Tec is counteracted by Ptpn22, which physically interacts with and facilitates tyrosine dephosphorylation of c-Maf thereby attenuating its transcriptional activity. We further show that phosphorylation of Tyr21/92/131 of c-Maf is also critical for its recruitment to the IL-21 promoter and optimal production of this cytokine by TH17 cells. Thus, manipulating tyrosine phosphorylation of c-Maf through its kinases and phosphatases can have significant impact on TH cell-mediated immune responses.
authors.affiliation: Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Chih-Chun
authors.initials: CC
authors.lastname: Liu
authors.affiliation: Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Chen-Yen
authors.initials: CY
authors.lastname: Lai
authors.affiliation: Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Wei-Feng
authors.initials: WF
authors.lastname: Yen
authors.affiliation: Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Yu-Hsien
authors.initials: YH
authors.lastname: Lin
authors.affiliation: Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Hui-Hsin
authors.initials: HH
authors.lastname: Chang
authors.affiliation: Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Tzong-Shyuan
authors.initials: TS
authors.lastname: Tai
authors.affiliation: Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Yu-Jung
authors.initials: YJ
authors.lastname: Lu
authors.affiliation: Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Hsiao-Wei
authors.initials: HW
authors.lastname: Tsao
authors.affiliation: Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: I-Cheng
authors.initials: IC
authors.lastname: Ho
authors.affiliation: Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Shi-Chuen
authors.initials: SC
authors.lastname: Miaw
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D015847:Interleukin-4 / Q000235:genetics; D007378:Interleukins / Q000096:biosynthesis; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D051257:Proto-Oncogene Proteins c-maf / Q000378:metabolism*; D058504:Th17 Cells / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics; D020798:Two-Hybrid System Techniques; D000098546:Interleukin-21
chemical_list: D007378:Interleukins; D051257:Proto-Oncogene Proteins c-maf; D015847:Interleukin-4; D019000:Phosphotyrosine; C089848:Tec protein-tyrosine kinase; D011505:Protein-Tyrosine Kinases; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; C516766:Ptpn22 protein, mouse; D000098546:Interleukin-21