NDLI: Molecular mechanism of the Syk activation switch.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Tse, Joyce K. Y. Papp, Eva Giannetti, Anthony M. Gandhi, Shaan Tsang, Emily Ho, Hoangdung Shaw, David Bradshaw, J. Michael Dinh, Marie Wang, Sandra
Description	Author Affiliation: Tsang E ( Department of Inflammation Discovery, Roche Palo Alto LLC, Palo Alto, California 94304, USA.)
Abstract	Many immune signaling pathways require activation of the Syk tyrosine kinase to link ligation of surface receptors to changes in gene expression. Despite the central role of Syk in these pathways, the Syk activation process remains poorly understood. In this work we quantitatively characterized the molecular mechanism of Syk activation in vitro using a real time fluorescence kinase assay, mutagenesis, and other biochemical techniques. We found that dephosphorylated full-length Syk demonstrates a low initial rate of substrate phosphorylation that increases during the kinase reaction due to autophosphorylation. The initial rate of Syk activity was strongly increased by either pre-autophosphorylation or binding of phosphorylated immune tyrosine activation motif peptides, and each of these factors independently fully activated Syk. Deletion mutagenesis was used to identify regions of Syk important for regulation, and residues 340-356 of the SH2 kinase linker region were identified to be important for suppression of activity before activation. Comparison of the activation processes of Syk and Zap-70 revealed that Syk is more readily activated by autophosphorylation than Zap-70, although both kinases are rapidly activated by Src family kinases. We also studied Syk activity in B cell lysates and found endogenous Syk is also activated by phosphorylation and immune tyrosine activation motif binding. Together these experiments show that Syk functions as an 'OR-gate' type of molecular switch. This mechanism of switch-like activation helps explain how Syk is both rapidly activated after receptor binding but also sustains activity over time to facilitate longer term changes in gene expression.
ISSN	00219258
e-ISSN	1083351X
Journal	Journal of Biological Chemistry
Issue Number	47
Volume Number	283
Language	English
Publisher	American Society for Biochemistry and Molecular Biology (United States)
Publisher Date	2008-11-21
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Intracellular Signaling Peptides And Proteins Metabolism Protein-Tyrosine Kinases Amino Acid Motifs B-Lymphocytes Gene Deletion Immune System Chemistry Kinetics Models, Biological Mutagenesis Peptides Phosphorylation Spectrometry, Fluorescence Substrate Specificity Tyrosine ZAP-70 Protein-Tyrosine Kinase Biochemistry Molecular Biology
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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