Andrew M. Scharenberg, M.D.
Associate Professor, Pediatrics and
Adunct Associate Professor, Immunology

Department of Pediatrics
University of Washington
CHMC 1900 9th Avenue Box 359300-C9S
Seattle, WA 98195-9300
Tel: 206.987.7314
Fax: 206.987.7310
Email: andrewms@u.washington.edu

The Scharenberg Lab Homepage

Dr. Scharenberg received his medical degree from the University of North Carolina School of Medicine in 1990 and completed his residency at UNC Children's Hospital in 1993. He completed postdoctoral fellowships in the Pediatric Scientist Development Program at NIH and at the Division of Experimental Pathology, Beth Israel Hospital, before joining the faculty of Harvard Medical School as assistant professor in 1998. Dr. Scharenberg joined the faculty at the University of Washington in November 2000, and is also an attending physician at Children's Hospital and Regional Medical Center where he participates in the Immunodeficiency Clinic and the inpatient Immunology consult service. He was chosen as the American Pediatric Society/Society for Pediatric Research National Young Investigator Award winner in 2002.

Current laboratory research focuses:

1) Ion channel signaling pathways in immune cells. a. The role of ADP-ribose in regulation of calcium entry via TRPM2. We have recently demonstrated that the TRPM2 ion channel is expressed in immunologic cells and is gated specifically by ADP-ribose produced by mitochondria (Nature, 411: 590-595; 2001; J. Biol Chem 280(7):6138-48, 2005). As virtually nothing is known about the biochemistry of ADP-ribose, our understanding of the processes which utilize this pathway is also rudimentary. Our approach at present has been to focus on developing methods for the measurement of intracellular ADP-ribose, analyzing the relationship between oxidant stress and ADP-ribose, characterizing the phenotype of cells lacking a key enzyme for the breakdown of ADP-ribose, and analyzing the structure/function relationships of TRPM2. b. Characterization of a novel divalent cation entry pathway mediated by TRPM7. We have cloned a novel ion channel, designated TRPM7, which regulates the entry of all types of divalent cations into many types of cells, including all immune cell types so far analyzed. It is unique in having an intrinsic protein kinase domain of presently unknown function. We have recently demonstrated that this protein is a central regulator of magnesium homeostasis in immune cells (Cell, 2003, 114(2):191-200), and are presently focusing on understanding relationships between magnesium homeostasis, cell metabolism, and cell proliferation.

2) Use of homing endonucleases in targeted repair of genes responsible for primary immune deficiencies. A new approach to gene therapy involves targeted repair of a gene via the induction of a double strand break at or near the mutation site. We are pursusing two projects related to develping methods required for executing gene repair, which are now supported by an NIH Roadmap grant: a) Engineering of homing endonucleases to cleave at novel recognition sites. Homing endonucleases are rare cutting enzymes which are of potential use in inducing double strand breaks at desired sites, but techniques are needed to generate new homing endonucleases which cut at desired sites. This project aims to evaluate several approaches for modifying homing endonuclease cutting sites, and involves a collaboration between our group, David Baker's protein design group, Barry Stoddard's structural biology group, and Ray Monnat's homing endonuclease biology group. b) Construction of animal models for development of homing endonucleases for double strand break-induced gene repair of immune cells. Methods for use of homing endonucleases in gene repair are not presently optimized. This project will create an animal model for evaluation of methods for homing endonuclease and DNA repair template introduction into immune cells. This project is a collaboration with David Rawlings gene therapy group, Hans-Peter Kiem's stem cell transplantation and gene therapy group, and Nancy Maizels DNA repair group.

Students training in the Scharenberg Lab: Benjamin Buelow, Jordan Jarjour, Marcia Paddock

Selected publications:

Rawlings D.J.* and Scharenberg A.M.*, Park H., Wahl M.I., Lin S., KatoR., Witte O.N., and Kinet J-P., Activation of Bruton's tyrosine kinase by a transphosphorylation/autophosphorylation mechanism initiated by src family kinases, Science, 271:822-825, 1996.

Scharenberg, A.M., and Kinet, J-P., The emerging field of receptor-mediated inhibitory signaling: SHP or SHIP, Cell, 87, 961-964, 1996.

Gupta, N., Scharenberg, A.M., Burshtyn, D.N., Lioubin, M., Rohrschneider, L.R., Kinet, J-P., and Long, E.O., Killer cell inhibitory receptors and FcgRIIb1 utilize distinct negative signaling pathways, J. Exp. Med., 186:473-478, 1997.

El-Hillal O., Kurosaki T., Yamamura H., Kinet J-P., and Scharenberg A.M., Syk kinase activation by a src kinase-initiated activation loop phosphorylation chain reaction, Proc. Natl. Acad. Sci. (USA), 94:1919-1924,1997.

Scharenberg, A.M., El-Hillal, O., Fruman, D.A., Li, Z., Beitz, L.O. , Lin, S., Gout, I., Waterfield, M.D., Witte, O.N., Cantley, L.C., Rawlings, D.J., and Kinet, J-P., Phosphatidylinositol-3,4,5-trisphosphate controls calcium signaling by initiating Tec-kinase dependent activation of PLCg, Embo 17: 1961-1972, 1998.

Fluckiger, A.C., Lei, Z. Kato, R.M., Wahl, M.I., Ochs, H., Kinet, J-P.,Witte, O.N., Longnecker, R.,Scharenberg, A.M., and Rawlings, D.J., Regulation of sustained calcium influx by Tec family tyrosine kinases, Embo J., 17:1973-1985, 1998.

Scharenberg, A.M., and Kinet, J-P., PtdIns-3,4,5-P3: A regulatory nexus between tyrosine kinases and sustained calcium signals, Cell, 94(1):5-8,1998.

Anne-Laure Perraud, Andrea Fleig, Christopher A. Dunn, Alex Stokes, Qiqin Zhu, Reinhold Penner, Jean-Pierre Kinet, and Andrew M. Scharenberg. ADP-ribose gating of the LTRPC2 cation channel revealed by Nudix motif homology, Nature, 411:595-99, 2001.

Monica J.S. Nadler, Meredith C. Hemosura, Anne-Laure Perraud, Qiqin Zhu, Jean-Pierre Kinet, Reinhold Penner, Andrew M. Scharenberg, and Andrea Fleig. LTRPC7 is a MgATP-regulated divalent cation-selective channel requiredfor cell viability. (2001) Nature, 411:590-595.

Pierre Launay, Andrea Fleig, Anne-Laure Perraud, Andrew M. Scharenberg,, Reinhold Penner, & Jean-Pierre Kinet, TRPM4 is a Ca2+-activated non-selective cation channel mediating cell membrane depolarization. Cell, 2002,109(3):397-407.

Carsten Schmitz, Anne-Laure Perraud, Catherine O. Johnson, Kazunori Inabe, Megan K. Smith, Reinhold Penner, Tomohiro Kurosaki, Andrea Fleig, and Andrew M. Scharenberg. Regulation of vertebrate cellular magnesium homeostasis by TRPM7. Cell (2003) 114(2):191-200.

B. Shen, A-L Perraud, A.M.Scharenberg, and B. Stoddard. Crystal structure of the NUDT9 mitochondrial ADP-ribose pyrophosphatase. J. Mol. Biol, 12;332(2):385-98. 2003.

K. Saito, K.F. Tolias, A. Saci, H.B. Koon, L.A. Humphries, A.M. Scharenberg, D.J. Rawlings, J.P. Kinet, C.L. Carpenter. BTK regulates PtdIns-4,5-P2 synthesis: importance for calcium signaling and PI3K activity. Immunity. 2003 Nov;19(5):669-78.

R. Takezawa, C. Schmitz, P. Demeuse, A.M. Scharenberg, R. Penner, A. Fleig. Receptor-mediated regulation of the TRPM7 channel through its endogenous protein kinase domain.Proc. Natl. Acad. Sci. U S A. 2004 Apr 20;101(16):6009-14. Epub 2004 Apr 06.

A.L. Perraud, C.L. Takanishi, B. Shen, S. Kang, M.K. Smith, C. Schmitz, H.M. Knowles, D. Ferraris, W. Li, J. Zhang, B.L. Stoddard, A.M. Scharenberg. Accumulation of free ADP-ribose from mitochondria mediates oxidative stress-induced gating of TRPM2 cation channels. J. Biol. Chem. 2005 Feb 18;280(7):6138-48. [Epub ahead of print].

Matthews S.A., Liu P., Spitaler M., Olson E.N., McKinsey T.A., Cantrell D.A., Scharenberg A.M., Essential Role for Protein Kinase D Family Kinases in the Regulation of Class II Histone Deacetylases in B Lymphocytes, (2006) Mol. Cell. Biol, Feb. 2006, 26(4):1569-1577.

Song Y., Dayalu R., Matthews S.A., Scharenberg A.M.TRPML cation channels regulate the specialized lysosomal compartment of vertebrate B-lymphocytes. Eur J Cell Biol., 2006, 85(12):1253-64.

Grubisha O., Rafty L.A., Takanishi C.L., Xu X., Tong L., Perraud A.L., Scharenberg A.M., Denu J.M. Metabolite of SIR2 reaction modulates TRPM2 ion channel. J Biol Chem, 2006, 19;281(20):14057-65.

Sahni J., Nelson B., Scharenberg A.M. SLC41A2 encodes a plasma membrane Mg 2+ transporter. Biochem J. , 2007 , 401(2):505-13.

Volna P., Jarjour J., Baxter S., Roffler S.R., Monnat R.J., Stoddard B.L., Scharenberg A.M. Flow cytometric analysis of DNA binding and cleavage by cell surface-displayed homing endonucleases. Nucleic Acids Research, 2007, 35(8):2748-2758.

Liu P, Scharenberg AM, Cantrell DA, Matthews SA. Protein kinase D enzymes are dispensable for proliferation, survival and antigen receptor-regulated NFkappaB activity in vertebrate B-cells.FEBS Lett. 2007, 581(7):1377-1382.

Scharenberg, AM, Humphries, LA, Rawlings D.J. Ca2+ signaling and Cell Fate Choice in B-cells. Nature Reviews in Immunoogy, Volume 7, October 2007, in press.

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Updated 8/29/07