Martin C. Schmidt, Ph.D.
Dept. Microbiology and Molecular Genetics
University of Pittsburgh School of Medicine
Pittsburgh, PA 15261
(412) 648-9243 Office
(412) 648-9380 Lab
mcs2@pitt.edu

Research Interests | Lab Members | Martin's Oligo Mutator
My lab studies the Snf1 kinase of yeast. The mammalian homologue of Snf1 is the AMP-activated protein kinase, an important therapeutic target for type II diabetes. Biochemical and genetic experiments have shown that Snf1 kinase is regulated by phosphorylation of the conserved threonine residue in the kinase activation loop. We have developed a phosphopeptide antibody that specifically recognizes the phosphorylated (active) form of Snf1 kinase. We have used the antibody to demonstrate that Snf1 is activated by three distinct upstream kinases called Sak1, Tos3 and Elm1. We now know that the Snf1-activating kinases are not themselves regulated by glucose. Instead, it is the DEphosphorylation of the Snf1 activation loop that responds to changes in glucose abundance. The yeast PP1 phosphatase is responsible for the dephosphorylation of Snf1 in response to changes in carbon source. We have shown that the PP1 phosphatase is active in low glucose toward most substrates. However, the Snf1 kinase becomes resistant to dephosphorylation. These data indicate that the active Snf1 kinase can adopt a phosphatase resistant structure. The phosphatase resistant structure is stabilized in vitro by binding low energy adenylate ligands such as AMP and ADP. In this way, the Snf1 kinase is a direct sensor of the cell's energy status with low energy adenylate ligands stabilizing the active form of Snf1 which then promotes ATP synthesis and conservation.

The long term goal of the lab is to identify all the components of the glucose signaling pathway in yeast and to understand how they interact in order to regulate gene expression and cellular metabolism. These studies will provide a better understanding of glucose-mediated regulation of cellular metabolism and have important implications for designing novel treatments for patients with diabetes.



Publications:

Chandrashekarrapa, D., R. R. McCartney and M. C. Schmidt (2011)
"Subunit and Domain Requirements for Adenylate-Mediated Protection of Snf1 Activation Loop from Dephosphorylation" J. Biological Chemistry 286:44532-44541.
Abstract

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Mayer, F.V., R. Heath, E. Underwood, M. J. Sanders, D. Carmena, R. R. McCartney, F. C. Leiper, B. Xiao, C. Jing, P. A. Walker, L. F. Haire, R. Ogrodowicz, S. R. Martin, M. C. Schmidt, S. J. Gamblin and D. Carling (2011)
"ADP regulates SNF1, the Saccharomyces cerevisiae homologue of AMP-activated protein kinase" Cell Metabolism 14: 707-714.
Abstract

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Supplement

Zhang, Y., R. R. McCartney, D. G. Chandrashekarappa, S. Mangat and M. C. Schmidt (2011)
"Reg1 protein regulates phosphorylation all three Snf1 isoforms but preferentially associates with the Gal83 isoform" Eukaryotic Cell 10: 1628-1636.
Abstract

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Rubenstein, E.M. & M.C. Schmidt (2010) "The glucose signal and metabolic p[H+]lux" EMBO J. 29:2473-2474. Download PDF file
Tabba,S., S. Mangat, R.R. McCartney & M.C. Schmidt (2010)
"PP1 phosphatase-binding motif in Reg1 protein of Saccharomyces cerevisiae is required for interaction with both the PP1 phosphatase Glc7 and the Snf1 protein kinase" Cellular Signalling 22:1013-1021.
Abstract

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S. Mangat, D. Chandrashekarappa, R.R. McCartney, K. Elbing and Martin C. Schmidt (2010) "Differential Roles of the Beta Subunit Glycogen-Binding Domains in the Regulation of the Snf1 Kinase Complex" Eukaryotic Cell 9: 173-183. Abstract

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Shirra,M.K., R.R. McCartney, C. Zhang, K.M. Shokat, M.C. Schmidt and K.M. Arndt (2008)
"A Chemical-Genomics Study Identifies Snf1 as a Repressor of Gcn4 Translation" J. Biological Chemistry 283: 35889-35898.
Abstract

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Rubenstein, E.M., R.R. McCartney, C. Zhang, K.M. Shokat, M.K. Shirra, K.M. Arndt and M.C. Schmidt (2008)
"Access Denied: Snf1 Activation Loop Phosphorylation is Controlled by Availability of the Phosphorylated Threonine 210 to the PP1 Phosphatase" J. Biological Chemistry 283: 222-230.
Abstract

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Rubenstein, E.M. and M.C. Schmidt (2007)
"Mechanisms regulating the protein kinases of Saccharomyces cerevisiae" Eukaryotic Cell 6: 571-583.
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Elbing, K., E.M. Rubenstein, R.R. McCartney and M.C. Schmidt (2006)
"Subunits of the SNF1 kinase heterotrimer show interdependence for association and activity" J. Biological Chemistry 281:26170-26180.
Abstract

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Rubenstein, E.M., R.R. McCartney and M.C. Schmidt (2006)
"Regulatory Domains of the Snf1-Activating Kinases Determine Pathway Specificity" Eukaryotic Cell 5: 620-627.
Abstract

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Elbing, K., R.R. McCartney and M.C. Schmidt (2006)
"Purification and Characterization of the three Snf1-activating kinases of Saccharomyces cerevisiae"
Biochemical Journal 393:, 797-805.
Abstract

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Ptacek, J., et al. (2005)
"Global Analysis of Protein Phosphorylation in Yeast"
Nature 438: 679-684.
Abstract

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McCartney, R.R., E.M. Rubenstein and M.C. Schmidt (2005)
"Snf1 kinase complexes with different beta subunits display stress-dependent preferences for the three Snf1-activating kinases"
Current Genetics 47: 335-344.
Abstract

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Sutherland, C. M., S.A. Hawley, R.R. McCartney, A. Leech, M.J.R. Stark, M.C. Schmidt, and D. G. Hardie (2003)
"Elm1p Is One of Three Upstream Kinases for the Saccharomyces cerevisiae SNF1 complex"
Current Biology 13:1299-1305.
Abstract

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Nath, N., R.R. McCartney and M. C. Schmidt (2003) "Yeast PAK1 Kinase Associates with and Activates Snf1" Molecular and Cellular Biology 23: 3909-3917. Abstract

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A. Leech, N. Nath, R.R. McCartney, and M. C. Schmidt (2003)
"Isolation of mutations in the catalytic domain of the Snf1 kinase that render its activity independent of the Snf4 subunit"
Eukaryotic Cell 2:265-273.
Abstract

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Nath, N., R. R. McCartney and M. C. Schmidt (2002)
"Purification and characterization of Snf1 kinase complexes containing a defined beta subunit composition"
J. Biological Chemistry 277:50403-50408.
Abstract

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McCartney, R. R. and Schmidt, M. C. (2001)
"Regulation of Snf1 kinase: activation requires phosphorylation of threonine 210 by an upstream kinase as well as a distinct step mediated by the Snf4 subunit"
J. Biological Chemistry 276:36460-36466

Abstract

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Schmidt, M. C. and R.R. McCartney (2000)
"Beta Subunits of Snf1 Kinase are required for kinase function and substrate definition."
EMBO Journal 19: 4936-4943.

Abstract

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Schmidt, M. C., R.R. McCartney, X. Zhang, T.S. Tillman, H. Solimeo, S. Wolfl, C. Almonte, & S. Watkins. (1999)
"Std1 and Mth1 proteins interact with the glucose sensors to control glucose-regulated gene expression in Saccharomyces cerevisiae".
Molecular and Cellular Biology 19:4561-4571.
Abstract

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Quinn, J., A.M. Fryberg, R.W. Ganster, M.C. Schmidt, and C.L. Peterson (1996)
"DNA Binding properties of the yeast SWI/SNF complex."
Nature, 379:844-847.
Abstract

Current Lab Members:


Rhonda McCartney
rorhonda@hotmail.com

Shadi Tabba, M.D.
Shadi.Tabba@chp.edu

Daksha Chandrashekarappa
dakshayinichethan@gmail.com

Simman Mangat, M.D.
drsbajwa@yahoo.co.in
Rotation Students

Beth Delorme-Axford
ebd7@pitt.edu

Prince Awuah
pak1@pitt.edu

Former Lab Members


Karin Elbing, Ph.D.
karin_elbing@yahoo.se

VJ Rubenstein, Ph.D.
yajeev80@yahoo.com

Annie Bedison
bedisonma@upmc.edu

Pavol Ganzor
pavol.genzor@email.stvincent.edu