Počet záznamů: 1
Positive and Negative Regulatory Roles of C-Terminal Src Kinase (CSK) in FcεRI-Mediated Mast Cell Activation, Independent of the Transmembrane Adaptor PAG/CSK-Binding Protein
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SYSNO ASEP 0497049 Druh ASEP J - Článek v odborném periodiku Zařazení RIV J - Článek v odborném periodiku Poddruh J Článek ve WOS Název Positive and Negative Regulatory Roles of C-Terminal Src Kinase (CSK) in FcεRI-Mediated Mast Cell Activation, Independent of the Transmembrane Adaptor PAG/CSK-Binding Protein Tvůrce(i) Potůčková, Lucie (UMG-J)
Dráberová, Lubica (UMG-J) RID
Hálová, Ivana (UMG-J) RID, ORCID
Paulenda, Tomáš (UMG-J)
Dráber, Petr (UMG-J) RIDČíslo článku 1771 Zdroj.dok. Frontiers in Immunology. - : Frontiers Media - ISSN 1664-3224
Roč. 9, August (2018)Poč.str. 21 s. Jazyk dok. eng - angličtina Země vyd. CH - Švýcarsko Klíč. slova mast cell ; degranulation ; cytokines ; C-terminal Src kinase ; phosphoprotein associated with glycosphingolipid-enriched microdomains ; LYN ; SHP-1 ; STAT5 Vědní obor RIV EB - Genetika a molekulární biologie Obor OECD Endocrinology and metabolism (including diabetes, hormones) CEP GA301/09/1826 GA ČR - Grantová agentura ČR GA14-09807S GA ČR - Grantová agentura ČR GA17-20255S GA ČR - Grantová agentura ČR GA17-20915S GA ČR - Grantová agentura ČR GA18-18521S GA ČR - Grantová agentura ČR Institucionální podpora UMG-J - RVO:68378050 UT WOS 000440588000001 Anotace C-terminal Src kinase (CSK) is a major negative regulator of Src family tyrosine kinases (SFKs) that play critical roles in immunoreceptor signaling. CSK is brought in contiguity to the plasma membrane-bound SFKs via binding to transmembrane adaptor PAG, also known as CSK-binding protein. The recent finding that PAG can function as a positive regulator of the high-affinity IgE receptor (FcεRI)-mediated mast cell signaling suggested that PAG and CSK have some non-overlapping regulatory functions in mast cell activation. To determine the regulatory roles of CSK in FcεRI signaling, we derived bone marrow-derived mast cells (BMMCs) with reduced or enhanced expression of CSK from wild-type (WT) or PAG knockout (KO) mice and analyzed their FcεRI-mediated activation events. We found that in contrast to PAG-KO cells, antigen-activated BMMCs with CSK knockdown (KD) exhibited significantly higher degranulation, calcium response, and tyrosine phosphorylation of FcεRI, SYK, and phospholipase C. Interestingly, FcεRI-mediated events in BMMCs with PAG-KO were restored upon CSK silencing. BMMCs with CSK-KD/PAG-KO resembled BMMCs with CSK-KD alone. Unexpectedly, cells with CSK-KD showed reduced kinase activity of LYN and decreased phosphorylation of transcription factor STAT5. This was accompanied by impaired production of proinflammatory cytokines and chemokines in antigen-activated cells. In line with this, BMMCs with CSK-KD exhibited enhanced phosphorylation of protein phosphatase SHP-1, which provides a negative feedback loop for regulating phosphorylation of STAT5 and LYN kinase activity. Furthermore, we found that in WT BMMCs SHP-1 forms complexes containing LYN, CSK, and STAT5. Altogether, our data demonstrate that in FcεRI-activated mast cells CSK is a negative regulator of degranulation and chemotaxis, but a positive regulator of adhesion to fibronectin and production of proinflammatory cytokines. Some of these pathways are not dependent on the presence of PAG. Pracoviště Ústav molekulární genetiky Kontakt Nikol Škňouřilová, nikol.sknourilova@img.cas.cz, Tel.: 241 063 217 Rok sběru 2019
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