Distinguished Professor of Pharmacology, Cellular & Molecular Medicine and Chemistry & Biology
Associate Vice Chancellor of Scientific Affairs
Key Words: Protein Tyrosine Phosphatases (PTPases)
Cells are highly responsive to signals from their environment. These signals include growth factors, neuronal firing, or even the presence of bacteria or pathogens that have invaded the body. The sensing and processing of these signals are carried out by molecular circuits within the cell that detect, amplify, and integrate the signals into a specific response. One of the most widely used cellular responses to environmental signals is to change the phosphorylation state of specific proteins. The level of phosphorylation of a protein is governed by two families of enzymes: protein kinases and protein phosphatases. My laboratory is interested in deciphering the role of protein phosphatases in various cellular paradigms, as phosphatases play key roles in processes such as the development of cancer, axonal pathfinding, and bacterial pathogenesis. Recently, we have expanded our work to include kinases and have identified a family of atypical “secreted” kinases that constitute a novel branch within the human kinome tree. The Fam20-family of kinases appears to be responsible for the phosphorylation of majority of the extracellular proteins and proteoglycans. What defines these kinases is the presence of a signal peptide that directs these enzymes to the secretory pathway where they phosphorylate ER/Golgi resident proteins, extracellular domains of cell surface receptors, xylose residues within the glycosaminoglycan-protein linkage and secreted proteins such as hormones or growth factors. These kinases are very important in a wide variety of cellular paradigms in which extracellular phosphorylation plays vital and as yet unappreciated roles.
Zhang J, Guan Z, Murphy AN, Wiley SE, Perkins GA, Worby CA, Engel JL, Heacock P, Nguyen OK, Wang JH, Raetz CR, Dowhan W, Dixon JE. Mitochondrial phosphatase PTPMT1 is essential for cardiolipin biosynthesis. Cell Metab. 2011 Jun 8;13(6):690-700. PMID: 21641550
Tagliabracci VS, Engel JL, Wen J, Wiley SE, Worby CA, Kinch LN, Xiao J, Grishin NV, Dixon JE. Secreted kinase phosphorylates extracellular proteins that regulate biomineralization. Science. 2012 Jun 1;336(6085):1150-3. PMID: 22582013
Xiao J, Tagliabracci VS, Wen J, Kim SA, Dixon JE. Crystal structure of the Golgi casein kinase. Proc Natl Acad Sci U S A. 2013 Jun 25;110(26):10574-9. PMID: 23754375
Tagliabracci VS, Engel JL, Wiley SE, Xiao J, Gonzalez DJ, Nidumanda Appaiah H, Koller A, Nizet V, White KE, Dixon JE. Dynamic regulation of FGF23 by Fam20C phosphorylation, GalNAc-T3 glycosylation, and furin proteolysis. Proc Natl Acad Sci U S A. 2014 Apr 15;111(15):5520-5. doi: 10.1073/pnas.1402218111. Epub 2014 Mar 26. PMID: 24706917
Wen J, Xiao J, Rahdar M, Choudhury BP, Cui J, Taylor GS, Esko JD, Dixon JE. Xylose phosphorylation functions as a molecular switch to regulate proteoglycan biosynthesis. Proc Natl Acad Sci U S A. 2014 Nov 4;111(44):15723-8. doi: 10.1073/pnas.1417993111. Epub 2014 Oct 20. PMID: 25331875
Cui J, Xiao J, Tagliabracci VS, Wen J, Rahdar M, Dixon JE. A secretory kinase complex regulates extracellular protein phosphorylation. eLife 2015;10.7554/eLife.06120. doi:10.7554/eLife.06120.