Regulation of platelet derived growth factor signaling by leukocyte common antigen-related (LAR) protein tyrosine phosphatase: a quantitative phosphoproteomics study
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Date
2016
Authors
Sarhan, Adil R.
Patel, Trushar R.
Creese, Andrew J.
Tomlinson, MIchael G.
Hellberg, Carina
Heath, John K.
Hotchin, Neil A.
Cunningham, Debbie L.
Journal Title
Journal ISSN
Volume Title
Publisher
Elsevier
Abstract
Intracellular signaling pathways are reliant on protein phosphorylation events that are controlled by a balance of kinase and phosphatase activity. Although kinases have been extensively studied, the role of phosphatases in controlling specific cell signaling pathways has been less so. Leukocyte common antigen-related protein (LAR) is a member of the LAR subfamily of receptor-like protein tyrosine phosphatases (RPTPs). LAR is known to regulate the activity of a number of receptor tyrosine kinases, including platelet-derived growth factor receptor (PDGFR). To gain insight into the signaling pathways regulated by LAR, including those that are PDGF-dependent, we have carried out the first systematic analysis of LAR-regulated signal transduction using SILAC-based quantitative proteomic and phosphoproteomic techniques. We haveanalyzed differential phosphorylation between wild-type mouse embryo fibroblasts (MEFs) and MEFs in which the LAR cytoplasmic phosphatase domains had been deleted (LARΔP), and found a significant change in abundance of phosphorylation on 270 phosphosites from 205 proteins because of the absence of the phosphatase domains of LAR. Further investigation of specific LAR-dependent phosphorylation sites and enriched biological processes reveal that LAR phosphatase activity impacts on a variety of cellular processes, most notably regulation of the actin cytoskeleton. Analysis of putative upstream kinases that may play an intermediary role between LAR and the identified LAR-dependent phosphorylation events has revealed a role for LAR in regulating mTOR and JNK signaling.
Description
Open access article. Creative Commons Attribution 4.0 International license (CC BY 4.0) applies
Keywords
Leukocyte common antigen-related protein , LAR , Phosphatase , Cell signaling , Signaling pathways , Platelet
Citation
Sarhan, A. R., Patel, T. R., Creese, A. J., Tomlinson, M. G., Hellberg, C., Heath, J. K., Hotchin, N. A., & Cunningham, D. L. (2016). Regulation of platelet derived growth factor signaling by leukocyte common antigen-related (LAR) protein tyrosine phosphatase: A quantitative phosphoproteomics study. Molecular & Cellular Proteomics, 15(6), 1823-1836. https://doi.org/10.1074/mcp.M115.053652