Spleen Tyrosine Kinase Mediates EGFR Signaling to Regulate Keratinocyte Terminal Differentiation

Wu, Nan; Huang, Duen Yi; Wang, Li-Fang; Kannagi, Reiji; Fan, Yu; Lin, Wan-Wan

doi:10.1038/jid.2015.381

Cited by 28 publications

(38 citation statements)

References 35 publications

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“…A literature search revealed that approximately one third of genes that carried non-synonymous mutations had been reported in the context of skin physiology and keratinocyte proliferation [34–41]. Activation of CDK2 in mouse epidermis reportedly induces keratinocyte proliferation, however did not affect skin tumor development [42, 43] Also SYK has been shown to act as a negative regulator in epidermal keratinocyte differentiation and is also involved in EGFR signaling, which may contribute to its regulatory role in keratinocyte terminal differentiation [44]. NEDD4 is involved in the ΔNp63α-mediated suppression of nuclear PTEN in basal layer keratinocytes, whereas nuclear PTEN inhibits cell proliferation and mice with a keratinocyte-specific null mutation of Pten reportedly exhibit epidermal hyperplasia and hyperkeratosis [45, 46].…”

Section: Discussionmentioning

confidence: 99%

Genetic alterations in seborrheic keratoses

et al. 2017

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Seborrheic keratoses are common benign epidermal lesions that are associated with increased age and sun-exposure. Those lesions despite harboring multiple somatic alterations in contrast to malignant tumors appear to be genetically stable. In order to investigate and characterize the presence of recurrent mutations, we performed exome sequencing on DNA from one seborrheic keratosis lesion and corresponding blood cells from the same patients with follow up investigation of alterations identified by exome sequencing in 24 additional lesions from as many patients. In addition we investigated alterations in all lesions at specific genes loci that included FGFR3, PIK3CA, HRAS, BRAF, CDKN2A and TERT and DHPH3 promoters. The exome sequencing data indicated three mutations per Mb of the targeted sequence. The mutational pattern depicted typical UV signature with majority of alterations being C>T and CC>TT base changes at dipyrimidinic sites. The FGFR3 mutations were the most frequent, detected in 12 of 25 (48%) lesions, followed by the PIK3CA (32%), TERT promoter (24%) and DPH3 promoter mutations (24%). TERT promoter mutations associated with increased age and were present mainly in the lesions excised from head and neck. Three lesions also carried alterations in CDKN2A. FGFR3, TERT and DPH3 expression did not correlate with mutations in the respective genes and promoters; however, increased FGFR3 transcript levels were associated with increased FOXN1 levels, a suggested positive feedback loop that stalls malignant progression. Thus, in this study we report overall mutation rate through exome sequencing and show the most frequent mutations seborrheic keratosis.

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Section: Discussionmentioning

confidence: 99%

Genetic alterations in seborrheic keratoses

et al. 2017

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“…Using the meta-analysis derived atopic dermatitis transcriptome (MADAD) [26] as a reference core AD transcriptome, Pavel et al presented data which supported the usage of dual JAK/SYK inhibition in AD by showing a dose-dependent improvement of the transcriptomic profile. The rational of this approach refers to the inhibition of T cell polarization by JAK inhibition [239] as well as improvement of the terminal epidermal differentiation by SYK inhibitors [240]. Additionally, IL31 expression was reduced more efficiently by the dual inhibition approach than that seen in dupilumab treatment.…”

Section: Prognostics and Treatmentmentioning

confidence: 99%

Review—Current Concepts in Inflammatory Skin Diseases Evolved by Transcriptome Analysis: In-Depth Analysis of Atopic Dermatitis and Psoriasis

Schwingen

Kaplan

Kurschus

2020

IJMS

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During the last decades, high-throughput assessment of gene expression in patient tissues using microarray technology or RNA-Seq took center stage in clinical research. Insights into the diversity and frequency of transcripts in healthy and diseased conditions provide valuable information on the cellular status in the respective tissues. Growing with the technique, the bioinformatic analysis toolkit reveals biologically relevant pathways which assist in understanding basic pathophysiological mechanisms. Conventional classification systems of inflammatory skin diseases rely on descriptive assessments by pathologists. In contrast to this, molecular profiling may uncover previously unknown disease classifying features. Thereby, treatments and prognostics of patients may be improved. Furthermore, disease models in basic research in comparison to the human disease can be directly validated. The aim of this article is not only to provide the reader with information on the opportunities of these techniques, but to outline potential pitfalls and technical limitations as well. Major published findings are briefly discussed to provide a broad overview on the current findings in transcriptomics in inflammatory skin diseases.

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“…SYK is involved in several cytokine signalling pathways, including the Th17 pathway . It induces the production of CCL20, which attracts Th17 cells to the skin . SYK also acts as a negative regulator of keratinocyte differentiation, and gradually decreases during the terminal differentiation process owing to a cross‐regulation with epidermal growth factor receptor .…”

Section: Discussionmentioning

confidence: 99%

“…It induces the production of CCL20, which attracts Th17 cells to the skin . SYK also acts as a negative regulator of keratinocyte differentiation, and gradually decreases during the terminal differentiation process owing to a cross‐regulation with epidermal growth factor receptor . In addition, SYK is involved in the survival, proliferation, and activation of B lymphocytes and in differentiation of dendritic cells .…”

Section: Discussionmentioning

confidence: 99%

“…Spleen tyrosine kinase (SYK) and Janus kinase (JAK) are tyrosine kinases (TYKs) that play important roles in inflammatory processes . SYK is involved in the release of cytokines during the proinflammatory process, including IL‐1β, IL‐10 and IL‐17, and regulates dendritic cells, B lymphocytes and keratinocyte differentiation, suggesting that SYK inhibitors could improve inflammatory skin diseases with aberrant differentiation, such as AD . The JAK kinases family (JAK1, JAK2, JAK3 and TYK2) is also involved in signalling pathways of several cytokines involved in AD, such as IL‐4, IL‐13, IL‐31 and IL‐33 .…”

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confidence: 99%

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The oral Janus kinase/spleen tyrosine kinase inhibitorASN002 demonstrates efficacy and improves associated systemic inflammation in patients with moderate‐to‐severe atopic dermatitis: results from a randomized double‐blind placebo‐controlled study

Bissonnette

Maari

Forman³

et al. 2019

Br J Dermatol

108

105

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SummaryBackground ASN002 is an oral dual inhibitor of Janus kinase and spleen tyrosine kinase, which are involved in the pathogenesis of atopic dermatitis (AD) through their regulatory role on T helper (Th)1, Th2 and Th17/Th22 pathways.ObjectivesThe objectives of this study were to evaluate the efficacy, safety, pharmacokinetics and effects on systemic biomarkers of ASN002 in patients with moderate‐to‐severe AD. Methods A total of 36 patients with moderate‐to‐severe AD were randomized (3 : 1) to ASN002 or placebo in the phase Ib study. Three dosage cohorts were studied over a 28‑day period (20 mg, 40 mg and 80 mg once daily).Results ASN002 was superior to placebo for the proportion of patients achieving Eczema Area and Severity Index (EASI) 50 (20 mg 20%, P = 0·93; 40 mg 100%, P = 0·003; 80 mg 83%, P = 0·03; placebo 22%), EASI 75 (20 mg 0%, P = 0·27; 40 mg 71%, P = 0·06; 80 mg 33%, P = 0·65; placebo 22%) and in change from baseline in pruritus (20 mg −1·3 ± 2·1, P = 0·81; 40 mg −3·1 ± 2·7, P = 0·27; 80 mg −4·7 ± 2·1, P = 0·01; placebo −1·6 ± 1·8). Adverse events were generally mild and similar across all groups. ASN002 showed dose‐dependent plasma exposure with low interpatient variability, significantly downregulated several serum biomarkers involved in Th1, Th2 and Th17/Th22 immunity, and decreased the atherosclerosis‐associated biomarker E selectin/SELE.ConclusionsIn patients with moderate‐to‐severe AD, ASN002 showed strong efficacy with rapid onset of action and associated improvements in systemic inflammation.

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Spleen Tyrosine Kinase Mediates EGFR Signaling to Regulate Keratinocyte Terminal Differentiation

Cited by 28 publications

References 35 publications

Genetic alterations in seborrheic keratoses

Genetic alterations in seborrheic keratoses

Review—Current Concepts in Inflammatory Skin Diseases Evolved by Transcriptome Analysis: In-Depth Analysis of Atopic Dermatitis and Psoriasis

The oral Janus kinase/spleen tyrosine kinase inhibitorASN002 demonstrates efficacy and improves associated systemic inflammation in patients with moderate‐to‐severe atopic dermatitis: results from a randomized double‐blind placebo‐controlled study

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