دورية أكاديمية
A reevaluation of the spleen tyrosine kinase (SYK) activation mechanism.
| العنوان: | A reevaluation of the spleen tyrosine kinase (SYK) activation mechanism. |
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| المؤلفون: | Mansueto MS; From the Departments of Pharmacology and., Reens A; From the Departments of Pharmacology and., Rakhilina L; From the Departments of Pharmacology and., Chi A; Chemical Biology, Merck & Co., Inc., Boston, Massachusetts 02115., Pan BS; From the Departments of Pharmacology and., Miller JR; From the Departments of Pharmacology and james.miller2@merck.com. |
| المصدر: | The Journal of biological chemistry [J Biol Chem] 2019 May 10; Vol. 294 (19), pp. 7658-7668. Date of Electronic Publication: 2019 Mar 28. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Country of Publication: United States NLM ID: 2985121R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1083-351X (Electronic) Linking ISSN: 00219258 NLM ISO Abbreviation: J Biol Chem Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2021- : [New York, NY] : Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Original Publication: Baltimore, MD : American Society for Biochemistry and Molecular Biology |
| مواضيع طبية MeSH: | Models, Chemical*, Syk Kinase/*chemistry, Amino Acid Motifs ; Enzyme Activation ; Humans ; Phosphorylation ; Proto-Oncogene Mas ; Syk Kinase/metabolism ; src Homology Domains ; src-Family Kinases/chemistry ; src-Family Kinases/metabolism |
| مستخلص: | Spleen tyrosine kinase (SYK) is a signaling node in many immune pathways and comprises two tandem Src homology (SH) 2 domains, an SH2-kinase linker, and a C-terminal tyrosine kinase domain. Two prevalent models of SYK activation exist. The "OR-gate" model contends that SYK can be fully activated by phosphorylation or binding of its SH2 domains to a dual-phosphorylated immune-receptor tyrosine-based activation motif (ppITAM). An alternative model proposes that SYK activation requires ppITAM binding and phosphorylation of the SH2-kinase linker by a SRC family kinase such as LYN proto-oncogene, SRC family tyrosine kinase (LYN). To evaluate these two models, we generated directly comparable unphosphorylated (upSYK) and phosphorylated (pSYK) proteins with or without an N-terminal glutathione S -transferase (GST) tag, resulting in monomeric or obligatory dimeric SYK, respectively. We assessed the ability of a ppITAM peptide and LYN to activate these SYK proteins. The ppITAM peptide strongly activated GST-SYK but was less effective in activating upSYK untagged with GST. LYN alone activated untagged upSYK to a greater extent than did ppITAM, and inclusion of both proteins rapidly and fully activated upSYK. Using immunoblot and phosphoproteomic approaches, we correlated the kinetics and order of site-specific SYK phosphorylation. Our results are consistent with the alternative model, indicating that ppITAM binding primes SYK for rapid LYN-mediated phosphorylation of Tyr-352 and then Tyr-348 of the SH2-kinase linker, which facilitates activation loop phosphorylation and full SYK activation. This gradual activation mechanism may also explain how SYK maintains ligand-independent tonic signaling, important for B-cell development and survival. (© 2019 Mansueto et al.) |
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| فهرسة مساهمة: | Keywords: ITAM (immune-receptor tyrosine activation motif); autophosphorylation; cell signaling; conformational change; enzyme activation; enzyme kinetics; immunity; non-receptor tyrosine kinase (nRTK); phosphorylation; spleen tyrosine kinase (SYK); tonic signalling |
| المشرفين على المادة: | 0 (MAS1 protein, human) 0 (Proto-Oncogene Mas) EC 2.7.10.2 (SYK protein, human) EC 2.7.10.2 (Syk Kinase) EC 2.7.10.2 (lyn protein-tyrosine kinase) EC 2.7.10.2 (src-Family Kinases) |
| تواريخ الأحداث: | Date Created: 20190330 Date Completed: 20191209 Latest Revision: 20211204 |
| رمز التحديث: | 20240628 |
| مُعرف محوري في PubMed: | PMC6514621 |
| DOI: | 10.1074/jbc.RA119.008045 |
| PMID: | 30923129 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1083-351X |
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| DOI: | 10.1074/jbc.RA119.008045 |