Syk Mediates IL−17-Induced CCL20 Expression by Targeting Act1-Dependent K63-Linked Ubiquitination of TRAF6

Wu, Nan; Huang, Duen Yi; Tsou, Hsin Ni; Lin, Ying; Lin, Wan-Wan

doi:10.1038/jid.2014.383

Cited by 62 publications

(54 citation statements)

References 53 publications

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“…Upon IL-17 stimulation, Syk associated with IL-17RA, Act1 and TRAF6, leading to activation of NF-κB [81]. Thus, there may be multiple avenues by which IL-17 activates NF-κB.…”

Section: Il-17 Signal Transductionmentioning

confidence: 99%

IL-17 Signaling: The Yin and the Yang

Amatya

Garg

Gaffen

2017

Trends in Immunology

588

473

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Interleukin (IL)-17 is the founding member of a novel family of inflammatory cytokines. While the pro-inflammatory properties of IL-17 are key to its host-protective capacity, unrestrained IL-17 signaling is associated with immunopathology, autoimmune disease and cancer progression. In this review, we discuss both the activators and the inhibitors of IL-17 signal transduction, and the physiological implications of these events. We highlight the surprisingly diverse means by which these regulators control expression of IL-17-dependent inflammatory genes, as well as the major target cells that respond to IL-17 signaling.

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“…Upon IL-17 stimulation, Syk associated with IL-17RA, Act1 and TRAF6, leading to activation of NF-κB [81]. Thus, there may be multiple avenues by which IL-17 activates NF-κB.…”

Section: Il-17 Signal Transductionmentioning

confidence: 99%

IL-17 Signaling: The Yin and the Yang

Amatya

Garg

Gaffen

2017

Trends in Immunology

588

473

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“…TRAF3IP2 interacts with TRAF6 and is important for NF-κB activation downstream of IL-17 receptor signaling [64-66]. TRAF3IP2 is also important for CCL20 production from keratinocytes in response to IL-17 [67]. A coding alteration in TRAF3IP2 is associated with both psoriasis vulgaris and psoriatic arthritis.…”

Section: Innate Immunitymentioning

confidence: 99%

The immunogenetics of Psoriasis: A comprehensive review

Harden

Krueger

Bowcock

2015

Journal of Autoimmunity

523

401

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Psoriasis vulgaris is a common, chronic inflammatory skin disease with a complex etiology involving genetic risk factors and environmental triggers. Here we describe the many known genetic predispositions of psoriasis with respect to immune genes and their encoded pathways in psoriasis susceptibility. These genes span an array of functions that involve antigen presentation (HLA-Cw6, ERAP1, ERAP2, MICA), the IL-23 axis (IL12Bp40, IL23Ap19, IL23R, JAK2, TYK2), T-cell development and T-cells polarization (RUNX1, RUNX3, STAT3, TAGAP, IL4, IL13), innate immunity (CARD14, c-REL, TRAF3IP2, DDX58, IFIH1), and negative regulators of immune responses (TNIP1, TNFAIP3, NFKBIA, ZC3H12C, IL36RN, SOCS1). The contribution of some of these gene products to psoriatic disease has also been revealed in recent years through targeting of key immune components, such as the Th17/IL-23 axis which has been highly successful in disease treatment. However, many of the genetic findings involve immune genes with less clear roles in psoriasis pathogenesis. This is particularly the case for those genes involved in innate immunity and negative regulation of immune specific pathways. It is possible that risk alleles of these genes decrease the threshold for the initial activation of the innate immune response. This could then lead to the onslaught of the pathogenic adaptive immune response known to be active in psoriatic skin. However, precisely how these various genes affect immunobiology need to be determined and some are speculated upon in this review. These novel genetic findings also open opportunities to explore novel therapeutic targets and potentially the development of personalized medicine, as well as discover new biology of human skin disease.

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“…In addition, our immunohistochemical study showed high expression of phosphorylated Syk in psoriatic epidermis samples. Our recent study also revealed that Syk mediates IL-17A-induced signaling to regulate chemokine C-C motif ligand 20 (CCL20) expression in epidermal keratinocytes (Wu et al, 2015), implying potential roles of Syk inhibitors in the treatment of psoriasis. Additional studies are needed to determine the effects of diverse Syk inhibitors on the skin.…”

Section: Discussionmentioning

confidence: 83%

Spleen Tyrosine Kinase Mediates EGFR Signaling to Regulate Keratinocyte Terminal Differentiation

Huang

Wang

et al. 2016

Journal of Investigative Dermatology

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Spleen tyrosine kinase (Syk), a non-receptor tyrosine kinase, was initially identified as a crucial regulator in proximal immunoreceptor signaling. Additional studies have revealed its pleiotropic roles, and drugs targeting Syk are under development for inflammatory diseases. Syk expression in the skin has been detected, but its functions in the skin are still unknown. Here, we found that Syk phosphorylation and expression in primary human keratinocytes decrease gradually along with terminal differentiation. Human skin specimens showed similar in vivo patterns. Syk inhibitors or knockdown of Syk increased the expression of differentiation markers under in vitro differentiation models. Furthermore, EGFR activation prominently induced Syk phosphorylation, which could be inhibited by the EGFR inhibitor gefitinib or knockdown of EGFR. The Src inhibitor also partially attenuated EGF-induced phosphorylation of Syk. However, Syk inhibition suppressed EGF-induced phosphorylation of EGFR. Immunoprecipitation and confocal microscopy further revealed the increased molecular interaction between EGFR and Syk after EGF stimulation. This study unravels the role of Syk in EGFR-mediated signaling and reveals regulatory roles of Syk in keratinocyte differentiation, suggesting the clinical potential of topical or systemic Syk inhibitors in the treatment of skin diseases with aberrant differentiation.Journal of Investigative Dermatology accepted article preview online, 30 September 2015. doi:10.1038/jid.2015.381.

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Syk Mediates IL−17-Induced CCL20 Expression by Targeting Act1-Dependent K63-Linked Ubiquitination of TRAF6

Cited by 62 publications

References 53 publications

IL-17 Signaling: The Yin and the Yang

IL-17 Signaling: The Yin and the Yang

The immunogenetics of Psoriasis: A comprehensive review

Spleen Tyrosine Kinase Mediates EGFR Signaling to Regulate Keratinocyte Terminal Differentiation

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