title: Spleen Tyrosine Kinase Mediates EGFR Signaling to Regulate Keratinocyte Terminal Differentiation.
abstract: Spleen tyrosine kinase (Syk), a nonreceptor 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 decreased 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.
authors.affiliation: Department of Medicine, Mackay Medical College, New Taipei City, Taiwan; Department of Dermatology, Mackay Memorial Hospital, Taipei, Taiwan; Mackay Junior College of Medicine, Nursing, and Management, New Taipei City, Taiwan.
authors.forename: Nan-Lin
authors.initials: NL
authors.lastname: Wu
authors.affiliation: Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Duen-Yi
authors.initials: DY
authors.lastname: Huang
authors.affiliation: Department of Dermatology, National Taiwan University, Taipei, Taiwan.
authors.forename: Li-Fang
authors.initials: LF
authors.lastname: Wang
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Reiji
authors.initials: R
authors.lastname: Kannagi
authors.affiliation: Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Yu-Ching
authors.initials: YC
authors.lastname: Fan
authors.affiliation: Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan; Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan. Electronic address: wwllaura1119@ntu.edu.tw.
authors.forename: Wan-Wan
authors.initials: WW
authors.lastname: Lin
mesh_terms: D001707:Biopsy, Needle; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D012867:Skin / Q000166:cytology / Q000473:pathology; D000072377:Syk Kinase
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; C512478:EGFR protein, human; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase