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          Institute: MPI für molekulare Biomedizin     Collection: Jahrbuch 2018 (publ. 2017, arch)     Display Documents

ID: 744089.0, MPI für molekulare Biomedizin / Jahrbuch 2018 (publ. 2017, arch)
Unperturbed Immune Function despite Mutation of C-Terminal Tyrosines in Syk Previously Implicated in Signaling and Activity Regulation
Authors:Weis, V.; Konigsberger, S.; Amler, S.; Wienands, J.; Kiefer, F.
Date of Publication (YYYY-MM-DD):2017-11-01
Title of Journal:Mol Cell Biol
Issue / Number:21
Start Page:e00216
End Page:00217
Review Status:Internal review
Audience:Not Specified
Abstract / Description:The nonreceptor tyrosine kinase Syk, a central regulator of immune cell differentiation and activation, is a promising drug target for treatment of leukemia and allergic and inflammatory diseases. The clinical failure of Syk inhibitors underscores the importance of understanding the regulation of Syk function and activity. A series of previous studies emphasized the importance of three C-terminal tyrosines in Syk for kinase activity regulation, as docking sites for downstream effector molecules, and for Ca(2+) mobilization. Here, we investigated the roles of these C-terminal tyrosines in the mouse. Surprisingly, expression of a triple tyrosine-to-phenylalanine human Syk mutant, SYK(Y3F), was not associated with discernible signaling defects either in reconstituted DT40 cells or in B or mast cells from mice expressing SYK(Y3F) instead of wild-type Syk. Remarkably, lymphocyte differentiation, calcium mobilization, and 2,4,6-trinitrophenyl (TNP)-specific immune responses were unperturbed in SYK(Y3F) mice. These results emphasize the capacity of immune cells to compensate for specific molecular defects, likely using redundant intermolecular interactions, and highlight the importance of in vivo analyses for understanding cellular signaling mechanisms.
Free Keywords:Animals; B-Lymphocytes/cytology/*metabolism; Cell Differentiation; Cell Line; Gene Knock-In Techniques; Humans; Mast Cells/*metabolism; Mice; *Mutation; Phenylalanine/genetics; Signal Transduction; Syk Kinase/chemistry/*genetics/*metabolism; Tyrosine/genetics; BCR signaling; Syk; immunoreceptors; mast cells
External Publication Status:published
Document Type:Article
Communicated by:MPI für molekulare Biomedizin
Affiliations:MPI für molekulare Biomedizin
External Affiliations:Institute of Biostatistics and Clinical Research, Westfalischen Wilhelms-Universitat Munster, Munster, Germany. Universitatsmedizin Gottingen, Georg-August-Universitat, Abt. Zellulare und Molekulare Immunologie, Gottingen, Germany. Max Planck Institute for Molecular Biomedicine, Mammalian Cell Signaling Laboratory, Munster, Germany fkiefer@gwdg.de. European Institute for Molecular Imaging (EIMI), University of Munster, Munster, Germany.
Identifiers:ISSN:1098-5549 (Electronic) 0270-7306 (Linking) %R 10.1... [ID No:1]
URL:https://www.ncbi.nlm.nih.gov/pubmed/28760774 [ID No:2]
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