MK2 Signaling: Lessons on Tissue Specificity in Modulation of Inflammation  Nanna Fyhrquist, Sampsa Matikainen, Antti Lauerma  Journal of Investigative Dermatology  Volume 130, Issue 2, Pages 342-344 (February 2010) DOI: 10.1038/jid.2009.372 Copyright © 2010 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Canonical and noncanonical activation of the p38 pathway. The canonical inflammatory response is mediated by proinflammatory receptors such as Toll-like receptors (TLRs), and it is maintained by the endogenous cytokines IL-1 and tumor necrosis factor (TNF), which bind to their cognate receptors, IL-1R and TNFR. Receptor activation induces the recruitment of receptor-specific adaptor proteins that recruit protein kinases. Subsequently, multiprotein complexes, containing at least one adaptor, one ubiquitin ligase, and one upstream protein kinase, are transiently formed, resulting in the activation of NF-κB and mitogenactivated protein kinases (MAPKs). The illustration depicts only one of four known MAPK pathways, the p38 pathway. In adaptive immune responses, cell-type-specific receptors and nonreceptor tyrosine kinases feed into the innate inflammatory kinase network. T-cell-receptor (TCR)-mediated stimulation activates proximal tyrosine kinases such as lymphocyte cell–specific protein tyrosine kinase (LCK) and, subsequently, ZAP70, which phosphorylates p38 in a noncanonical fashion. Alternative activation of p38 is also mediated by TAB1-dependent autophosphorylation of p38. The nonreceptor, normally Fcγ-receptor-associated tyrosine kinase spleen tyrosine kinase (SYK), also stimulates inflammatory cytokine production. Type 1 IFNreceptor- associated Janus kinases (JAKs) can modulate inflammatory cytokine production, probably through different signal transducer and activator of transcription (STAT) signaling molecules. Targeting of MK2 by pharmacological inhibitors leaves intact the p38–TAB1 feedback control and the anti-inflammatory effects of downstream targets of p38, such as MSK1 and MSK2. However, MK2 inhibition abolishes any possible MK2-provided negative feedback for NF-κB signaling, and MK3 proinflammatory signaling remains. IFNR, IFN receptor; IKK, inhibitor of κβ kinase; IRAK, IL-1R-associated kinase; IRF, IFN regulatory factor; MKK, MAPK kinase; MSK, mitogen- and stress-activated protein kinase; RIP, receptor interacting protein; TAB, TAK-binding protein; TAK, transforming growth factor-β activated protein kinase; VEGF, vascular endothelial growth factor; ZAP-70, zeta chain–associated 70-kDa tyrosine phosphoprotein. Journal of Investigative Dermatology 2010 130, 342-344DOI: (10.1038/jid.2009.372) Copyright © 2010 The Society for Investigative Dermatology, Inc Terms and Conditions

Journal of Investigative Dermatology 2010 130, 342-344DOI: (10 Journal of Investigative Dermatology 2010 130, 342-344DOI: (10.1038/jid.2009.372) Copyright © 2010 The Society for Investigative Dermatology, Inc Terms and Conditions