title: Scaffold protein Dlgh1 coordinates alternative p38 kinase activation, directing T cell receptor signals toward NFAT but not NF-kappaB transcription factors.
abstract: Tyrosine kinases couple the T cell receptor (TCR) to discrete signaling cascades, each of which is capable of inducing a distinct functional outcome. Precisely how TCR signals are channeled toward specific targets remains unclear. TCR stimulation triggers 'alternative' activation of the mitogen-activated protein kinase p38, whereby the Lck and Zap70 tyrosine kinases directly activate p38. Here we report that alternatively activated p38 associated with the Dlgh1 MAGUK scaffold protein. 'Knockdown' of Dlgh1 expression blocked TCR-induced activation of p38 and the transcription factor NFAT but not of the mitogen-activated protein kinase Jnk or transcription factor NF-kappaB. A Dlgh1 mutant incapable of binding p38 failed to activate NFAT. Along with reports that the CARMA1 MAGUK scaffold protein coordinates activation of Jnk and NF-kappaB but not of p38 or NFAT, our findings identify MAGUK scaffold proteins as 'orchestrators' of TCR signal specificity.
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, California 90066, USA.
authors.forename: June L
authors.initials: JL
authors.lastname: Round
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Humphries
authors.forename: Tamar
authors.initials: T
authors.lastname: Tomassian
authors.forename: Paul
authors.initials: P
authors.lastname: Mittelstadt
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.forename: M Carrie
authors.initials: MC
authors.lastname: Miceli
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D000074288:Discs Large Homolog 1 Protein; D004789:Enzyme Activation; D051528:Guanylate Kinases; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000074288:Discs Large Homolog 1 Protein; C000614189:Dlg1 protein, mouse; D008565:Membrane Proteins; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D034741:RNA, Small Interfering; D011948:Receptors, Antigen, T-Cell; D048051:p38 Mitogen-Activated Protein Kinases; D051528:Guanylate Kinases