Tyrosine Kinases in Autoimmune and Inflammatory Skin Diseases

Szilveszter, Kata; Németh, Tamás; Mócsai, Attila

doi:10.3389/fimmu.2019.01862

Cited by 103 publications

(91 citation statements)

References 228 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Considering the central role of Syk in immune cells and platelets, its established role in many disease processes including myeloid malignancies [15,49,50], and its increasingly recognized role as a therapeutic target [51,52], it will be now very important to elucidate the precise mechanism via which Syk is controlled by S297 phosphorylation.…”

mentioning

confidence: 99%

Feedback Regulation of Syk by Protein Kinase C in Human Platelets

Makhoul

Dorschel

Gambaryan

et al. 2019

IJMS

View full text Add to dashboard Cite

The spleen tyrosine kinase (Syk) is essential for immunoreceptor tyrosine-based activation motif (ITAM)-dependent platelet activation, and it is stimulated by Src-family kinase (SFK)-/Syk-mediated phosphorylation of Y352 (interdomain-B) and Y525/526 (kinase domain). Additional sites for Syk phosphorylation and protein interactions are known but remain elusive. Since Syk S297 phosphorylation (interdomain-B) was detected in platelets, we hypothesized that this phosphorylation site regulates Syk activity via protein kinase C (PKC)-and cyclic adenosine monophosphate (cAMP)-dependent pathways. ADP, the GPVI-agonist convulxin, and the GPIbα-agonist echicetin beads (EB) were used to stimulate human platelets with/without effectors. Platelet aggregation and intracellular messengers were analyzed, along with phosphoproteins, by immunoblotting using phosphosite-specific antibodies or phos-tags. ADP, convulxin, and EB upregulated Syk S297 phosphorylation, which was inhibited by iloprost (cAMP pathway). Convulxin-stimulated Syk S297 phosphorylation was stoichiometric, transient, abolished by the PKC inhibitor GF109203X, and mimicked by the PKC activator PDBu. Convulxin/EB stimulated Syk S297, Y352, and Y525/526 phosphorylation, which was inhibited by SFK and Syk inhibitors. GFX and iloprost inhibited convulxin/EB-induced Syk S297 phosphorylation but enhanced Syk tyrosine (Y352/Y525/526) and substrate (linker adaptor for T cells (LAT), phospholipase γ2 (PLC γ2)) phosphorylation. GFX enhanced convulxin/EB-increases of inositol monophosphate/Ca2+. ITAM-activated Syk stimulates PKC-dependent Syk S297 phosphorylation, which is reduced by SFK/Syk/PKC inhibition and cAMP. Inhibition of Syk S297 phosphorylation coincides with enhanced Syk activation, suggesting that S297 phosphorylation represents a mechanism for feedback inhibition in human platelets.

show abstract

mentioning

confidence: 99%

Feedback Regulation of Syk by Protein Kinase C in Human Platelets

Makhoul

Dorschel

Gambaryan

et al. 2019

IJMS

View full text Add to dashboard Cite

show abstract

“…Also, an investigation of the effects of tofacitinib on the viral loads of Cytomegalovirus and Epstein-Barr virus pointed to no clinically significant effects of this JAK inhibitor [31]. The risk of infection during treatment with tofacitinib seems to be similar to that during treatment with biologics [6,9], and the overall benefit/risk profile of the drug when used for psoriasis appears to be comparable to those of other systemic treatments [32].…”

Section: Discussionmentioning

confidence: 99%

“…TYK2 inhibitors inhibit TYK2 function, which in turn suppresses intracellular signal transduction downstream of the receptor and thus further cytokine production through IL-23 during the psoriatic inflammation process hyperimmunoglobulin E syndrome. Furthermore, dysregulation of JAK signaling is seen in various autoimmune diseases [8,9].…”

Section: Jaks and Their Signaling Pathwaymentioning

confidence: 99%

See 1 more Smart Citation

Systemic Treatment of Psoriasis with JAK Inhibitors: A Review

Kvist-Hansen

Hansen

Skov

2019

Dermatol Ther (Heidelb)

View full text Add to dashboard Cite

Psoriasis is a prevalent chronic inflammatory disease. The inflammatory response is driven by T cells and mediated by multiple cytokines such as tumor necrosis factor and the interleukins IL-17 and IL-23. Moderate-to-severe psoriasis is treated systemically, using either biologics or conventional treatments with small-molecule drugs. The newer biologics are very effective and well tolerated, but not all patients respond to treatment with biologics, so there is a need for new treatment options for psoriasis. Janus kinase (JAK) inhibitors are a new drug class that may be of use in this respect. These inhibitors are already on the market for rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis. They block the intracellular signal pathway mediated by JAK and signal transducer and activator of transcription (STAT) proteins, thereby inhibiting gene transcription of proinflammatory cytokines. JAK inhibitors are currently being tested as potential treatments for psoriasis. They have shown clinical efficacy as measured by the Psoriasis Area and Severity Index 75 response in both phase 2 and 3 trials, and appear to be well tolerated overall. This review provides an overview of the mechanisms underlying the actions of JAK inhibitors in psoriasis, together with the results of clinical trials testing their efficacies when used to treat the disease.

show abstract

“…Anomalous regulation of this kinase could lead to different allergic disorders and antibody-mediated autoimmune diseases. Thus, Syk may serve as a therapeutically relevant target for rheumatoid arthritis, asthma, psoriasis, and allergic rhinitis [8][9][10]. It has been believed for years that Syk function is solely linked to hematopoietic cell signalling.…”

Section: Introductionmentioning

confidence: 99%

Synergistic Anti-Tumour Effect of Syk Inhibitor and Olaparib in Squamous Cell Carcinoma: Roles of Syk in EGFR Signalling and PARP1 Activation

Huang

Chen

et al. 2020

Cancers

View full text Add to dashboard Cite

Syk is a non-receptor tyrosine kinase involved in the signalling of immunoreceptors and growth factor receptors. Previously, we reported that Syk mediates epidermal growth factor receptor (EGFR) signalling and plays a negative role in the terminal differentiation of keratinocytes. To understand whether Syk is a potential therapeutic target of cancer cells, we further elucidated the role of Syk in disease progression of squamous cell carcinoma (SCC), which is highly associated with EGFR overactivation, and determined the combined effects of Syk and PARP1 inhibitors on SCC viability. We found that pharmacological inhibition of Syk could attenuate the EGF-induced phosphorylation of EGFR, JNK, p38 MAPK, STAT1, and STAT3 in A431, CAL27 and SAS cells. In addition, EGF could induce a Syk-dependent IL-8 gene and protein expression in SCC. Confocal microscopic data demonstrated the ability of the Syk inhibitor to change the subcellular distribution patterns of EGFR after EGF treatment in A431 and SAS cells. Moreover, according to Kaplan-Meier survival curve analysis, higher Syk expression is correlated with poorer patient survival rate and prognosis. Notably, both Syk and EGFR inhibitors could induce PARP activation, and synergistic cytotoxic actions were observed in SCC cells upon the combined treatment of the PARP1 inhibitor olaparib with Syk or the EGFR inhibitor. Collectively, we reported Syk as an important signalling molecule downstream of EGFR that plays crucial roles in SCC development. Combining Syk and PARP inhibition may represent an alternative therapeutic strategy for treating SCC.

show abstract

Tyrosine Kinases in Autoimmune and Inflammatory Skin Diseases

Cited by 103 publications

References 228 publications

Feedback Regulation of Syk by Protein Kinase C in Human Platelets

Feedback Regulation of Syk by Protein Kinase C in Human Platelets

Systemic Treatment of Psoriasis with JAK Inhibitors: A Review

Synergistic Anti-Tumour Effect of Syk Inhibitor and Olaparib in Squamous Cell Carcinoma: Roles of Syk in EGFR Signalling and PARP1 Activation

Contact Info

Product

Resources

About