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
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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 |
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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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| Rubenstein, E.M. and M.C. Schmidt (2007) "Mechanisms regulating the protein kinases of Saccharomyces cerevisiae" Eukaryotic Cell 6: 571-583. |
Download PDF file |
| 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 |
| 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 |
| Ptacek, J., et al.
(2005) "Global Analysis of Protein Phosphorylation in Yeast" Nature 438: 679-684. |
Abstract |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
McCartney, R. R. and Schmidt, M. C. (2001) |
Abstract |
Schmidt, M. C. and R.R. McCartney (2000) |
Abstract |
| 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 |
| 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 |
 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 |
 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 |