Martin C. Schmidt, Ph.D.
Larger view
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Martin C. Schmidt, Ph.D. |
Larger view |
Research Interests
| Lab Members ||
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 found this phosphorylation event
is catalyzed by three distinct upstream kinases called Sak1,
Tos3 and Elm1. However, 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. One ongoing project in the lab is understanding how the Snf1 kinase phosphorylation status is regulated. The yeast PP1 phosphatase is the primary phosphatase 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 homeostasis. A new project in the lab examines the genetics of 2-deoxyglucose (2DG) resistance. We found that yeast cells growing on glucose require Snf1 for resistance to 2DG. This finding was surprising since Snf1 kinase is thought to be largely inactive in cells growing on glucose. We found that while Snf1 is less active, that its activity is critical for 2DG resistance. Our studies have found that 2DG promotes the endocytosis of the hexose transporters 1 and 3 causing glucose starvation even when cells are in the presence of abundant glucose. Our findings have important implications for human cancer cells since these often rely on increased glucose transport and metabolism and are also sensitive to 2DG. 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.
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Selected Recent Publications
| Older
Publications
| Lesko, M.A., D.G. Chandrashekarappa, E.M. Jordahl, K.G. Oppenheimer, R.W.Bowman, C. Shang, J.D. Durrant,M.C. Schmidt and A.F. O'Donnell
(2023) "Changing course: Glucose starvation drives nuclear accumulation of Hexokinase 2 in S. cerevisiae" PLOS Genetics 19(5):e1010745. |
Abstract |
| Hellemann,E, J.L. Walker, M.A. Lesko, D.G. Chandrashekarappa, M.C. Schmidt, A.F. O'Donnell and J.D. Durrant (2022) "Novel mutation in hexokinase 2 confers resistance to 2-deoxyglucose by altering protein dynamics"PLOS Computational Biology:18(3):e1009929. |
Abstract |
| Barney, J. B., D.G. Chandrashekarappa, S.R. Soncini, and M. C. Schmidt (2021) "Drug resistance in diploid yeast is acquired through dominant alleles, haploinsufficiency, gene duplication and aneuploidy" PLOS Genetics: 17(9):e1009800 | Abstract |
| Schmidt M.C. and A.F O'Donnell (2021) "Sugarcoating 2-deoxyglucose: Mechanisms that suppress its toxic effects" Current Gentics 67: 107-114. |
Abstract |
| Soncini, S.R., D.G. Chandrashekarappa, D.A. Augustine, K.P. Callahan,
A.F. O'Donnell and M. C. Schmidt (2020) "Spontaneous mutations that confer resistance to 2-deoxyglucose act through Hxk2 and Snf1 pathways to regulate gene expression and HXT endocytosis" PLOS Genetics: 16(7):e1008484 | Abstract |
| O'Donnell, A.F. and M. C. Schmidt (2019) "Helping our daughters succeed: asymmetric distribution of glucose transporter mRNA" EMBO J. 38: e102063 |
Abstract |
| O'Donnell, A.F. and M. C. Schmidt
(2019) "AMPK-Mediated Regulation of Alpha-Arrestins and Protein Trafficking" Int J Mol Sci 25: E515 |
Abstract |
| Offley, S.R. and M. C. Schmidt (2018) "Protein Phosphatases of S. cerevisiae" Current Genetics 65: 41-55 |
Abstract |
| Chandrashekarappa, D.G., R.R. McCartney, A.F. O'Donnell and
M. C. Schmidt (2016) "The beta subunit of yeast AMP-activated protein kinase directs substrate specificity in response to alkaline stress" Cellular Signalling 28: 1881-1893 |
Abstract |
| McCartney, R.R., L. Garnar-Wortzel, D. G. Chandrashekarappa and
M. C. Schmidt (2016) "Activation and inhibition of Snf1 kinase activity by phosphorylation within the activation loop" BBA Proteins and Proteomics 1864: 1518-1528. |
Abstract |
| O'Donnell, A. F., R. R. McCartney, D. G. Chandrashekarappa,
B. B. Zhang, J. Thorner and M. C. Schmidt (2014)
"2-Deoxyglucose impairs yeast growth by stimulating Snf1-regulated and α-arrestin-mediated trafficking of hexose transporters 1 and 3 in Saccharomyces cerevisiae" Molecular and Cellular Biology 35: 939-955. |
Abstract |
| McCartney, Rhonda R., Dakshayini G. Chandrashekarappa, Bob B. Zhang
and
M. C. Schmidt (2014) "Genetic analysis of resistance and sensitivity to 2-deoxyglucose in Saccharomyces cerevisiae" Genetics 198: 635-646. |
Abstract |
| M. C. Schmidt
(2013) "Signaling Crosstalk: Integrating Nutrient Availability and Sex" Science Signaling 6(291):pe2889-98. |
Abstract |
| Chandrashekarrapa, D., R. R. McCartney and M. C. Schmidt
(2013) "Ligand Binding to the AMP-activated Protein Kinase Active Site Mediates Protection of the Activation Loop from Dephosphorylation" J. Biological Chemistry 288:89-98. |
Abstract |
| 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 |
| 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 |
| Mangat, S., 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 |
| 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 |
| 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 |
| Older Publications |
 Martin Schmidt mcs2 [at] pitt.edu |
 Daksha Chandrashekarappa dag77 [at] pitt.edu |
 Jordan Barney jbb58 [at] pitt.edu |  Luna Yang yay69 [at] pitt.edu |
 Yuxin Dong yud37 [at] pitt.edu |
 Rhonda McCartney |
 Sarah Offley |
 Samantha Soncini |
 Leo Garnar-Wortzel |
 Talia Levi |
 Marissa Avolio |
 Bob Zhang |
 Yuxun Zhang Ph.D. |
 Vaibhav Sharma |
 Beth Delorme-Axford Ph.D. |
 Prince Awuah Ph.D. |
 Shadi Tabba, M.D. |
 Simman Mangat, M.D. |
 Karin Elbing, Ph.D. |
 VJ Rubenstein, Ph.D. emrubenstein [at] bsu.edu |
 Annie Bedison |
 Pavol Ganzor |
 Nandita Nath Ph.D. |
 Ruhul Kuddus Ph.D. ruhul.kuddus [at] uvu.edu |
 Anna Leech |