Edward Y. Skolnik
Professor, Skirball Institute of Biomolecular Medicine, Molecular Pathogenesis; Norman S. Wikler Professor of Medicine; Director Division of Nephrology. Departments of Medicine and Biochemistry and Molecular Pharmacology
M.D., 1982 SUNY Health Sciences Center at Brooklyn
PI3 kinase, Potassium channels, Lymphocyte activation, histidine phosphorylation, NDPK.
Skirball Institute of Biomolecular Medicine
540 First Avenue 3rd floor, Lab 9
New York, N.Y. 10016
Office Tel: (212) 263-7458
Lab Tel: (212) 263-7456
Fax: (212) 263-8951
Tel: (212) 263-6281
Potassium channels and histidine phosphorylation / dephosphorylation in immune regulation and other processes.
Regulation and function of the K channel KCa3.1 and lymphocyte activation
The K+ channel, KCa3.1, is required for Ca2+ influx and the subsequent activation of T cells and mast cells. We have found that KCa3.1 is regulated by reversible lipid and histidine phosphorylation. These studies demonstrated that TCR and FcεRII crosslinking activates PI3K-C2β resulting in the generation of phosphatidylinositol 3 phosphate (PI(3)P), which functions to enable the histidine kinase, nucleoside diphosphate kinase B, to activate KCa3.1 by phosphorylation H358 in C-terminus of KCa3.1. In addition, we identified three new negative regulators of KCa3.1; the PI(3)P phosphatase myotubularin-related protein 6 and the histidine phosphatase, PHPT-1, which inhibit KCa3.1 by dephosphorylating PI(3)P and KCa3.1, respectively, and TRIM27 which ubiquitinates and inhibits PI3K-C2β. These findings provide one of the best examples whereby a mammalian histidine kinase and histidine phosphatase regulates a biological process in mammals. We are currently working to understand the mechanism(s) whereby these molecules are regulated in CD4 T cells and mast cells.
Inhibiting KCa3.1 is a potential treatment for autoimmune disease
We found that both Ca2+ influx and cytokine production by Th1 and Th2 CD4 T cells were impaired in KCa3.1-/- mice, while T-regulatory and Th17 function were normal. Moreovoer, KCa3.1-/- mice were protected from developing severe colitis in two mouse models of inflammatory bowel disease (IBD). Pharmacologic inhibitors of KCa3.1 have already been shown to be safe in humans. Thus, it may be possible to rapidly test whether KCa3.1 inhibitors are efficacious in patients with IBD.
Identification of other biological functions regulated by histidine phosphorylation
We still know very little about the identity of the kinases or phosphatases that regulate histidine phosphorylation in mammals, the protein targets that are histidine phosphorylated, or the biological consequences regulated by histidine phosphorylation. Our findings on KCa3.1, led us to identify other biological processes regulated by histidine phosphorylation. We recently found that TRPV5, a Ca2+ channel that is critical for maintaining whole body Ca2+ homeostasis by regulating Ca2+ reabsorption in the distal tubule of the kidney is also regulated by histidine phosphorylation in a manner similar to KCa3.1. In addition, studying PHPT-1-/- mice, we found that PHPT-1-/- mice are embryonically lethal prior to day 8.5 and that conditional deletion of PHPT-1 in number of different has led to interesting phenotypes. Our ongoing goals are to identify the specific signaling pathways regulated by histidine phosphorylation and that account for these phenotypes.
- Srivastava, S., Li, Z., Ko, K., Choudhury, P., Albaqumi, M., Johnson, A., Unutmaz, D., Backer J., and Skolnik, E.Y. Histidine phosphorylation of the potassium channel KCa3.1 by nucleoside diphosphate kinase B is required for activation of KCa3.1 and CD4 T cells. Molecular Cell (2006) 24:665-675. PMID: 17157250
- Srivastava, S., Zhdanova, O. Lie, Dl, Li, Z., Albaqumi, M., Wulff, H., and Skolnik, E.Y. Protein Histidine Phosphatase-1 negatively regulates CD4 T cells by inhibiting the K channel KCa3.1. PNAS, (2008) 105:14444-6. PMID: 18796614
- Di, L., Srivastava, S. Zhadnova, O., Ding, Y., Li, Z., Wulff, H., Lafaille, M., and Skolnik, E.Y. Inhibition of the K channel KCa3.1 ameliorates T cell mediated colitis. PNAS, (2010) 107:1541-6. PMID: 20080610
- Cai, X, Srivastava, S., Sun, Y., Li Z., Wu H., Zuvela-Jelaska L., Li J., Salamon R.S., Backer J.M., Skolnik E.Y. Tripartite motif containing protein 27 negatively regulates CD4 T cells by ubiquitinating and inhibiting the class II PI3K-C2β. PNAS, (2011) 108:20072-7. PMID: 22128329
- Srivastava, S., Cai, X., Li Z., Sun, Y., and Skolnik, E.Y. Phosphatidylinositol-3-kinase C2b and TRIM27 function to positively and negatively regulate IgE receptor activation on mast cells. Mol. Cell Biol. (2012) 32:31322-9. PMID: 22645315