Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

Science 316 (5821): 109-112

Copyright © 2007 by the American Association for the Advancement of Science

Regulation of a Cyclin-CDK-CDK Inhibitor Complex by Inositol Pyrophosphates

Young-Sam Lee,1 Sashidhar Mulugu,2 John D. York,2 Erin K. O'Shea1*

Abstract: In budding yeast, phosphate starvation triggers inhibition of the Pho80-Pho85 cyclin–cyclin-dependent kinase (CDK) complex by the CDK inhibitor Pho81, leading to expression of genes involved in nutrient homeostasis. We isolated myo-D-inositol heptakisphosphate (IP7) as a cellular component that stimulates Pho81-dependent inhibition of Pho80-Pho85. IP7 is necessary for Pho81-dependent inhibition of Pho80-Pho85 in vitro. Moreover, intracellular concentrations of IP7 increased upon phosphate starvation, and yeast mutants defective in IP7 production failed to inhibit Pho80-Pho85 in response to phosphate starvation. These observations reveal regulation of a cyclin-CDK complex by a metabolite and suggest that a complex metabolic network mediates signaling of phosphate availability.

1 Howard Hughes Medical Institute, Faculty of Arts and Sciences Center for Systems Biology, Department of Molecular and Cellular Biology, Harvard University, 7 Divinity Avenue, Cambridge, MA 02138, USA.
2 Howard Hughes Medical Institute, Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.

* To whom correspondence should be addressed. E-mail: erin_oshea{at}

Nucleotide degradation and ribose salvage in yeast.
Y.-F. Xu, F. Letisse, F. Absalan, W. Lu, E. Kuznetsova, G. Brown, A. A. Caudy, A. F. Yakunin, J. R. Broach, and J. D. Rabinowitz (2014)
Mol Syst Biol 9, 665
   Abstract »    Full Text »    PDF »
Yeast Phospholipase C Is Required for Normal Acetyl-CoA Homeostasis and Global Histone Acetylation.
L. Galdieri, J. Chang, S. Mehrotra, and A. Vancura (2013)
J. Biol. Chem. 288, 27986-27998
   Abstract »    Full Text »    PDF »
Regulation of Inositol Metabolism Is Fine-tuned by Inositol Pyrophosphates in Saccharomyces cerevisiae.
C. Ye, W. M. M. S. Bandara, and M. L. Greenberg (2013)
J. Biol. Chem. 288, 24898-24908
   Abstract »    Full Text »    PDF »
Phosphate-Activated Cyclin-Dependent Kinase Stabilizes G1 Cyclin To Trigger Cell Cycle Entry.
S. Menoyo, N. Ricco, S. Bru, S. Hernandez-Ortega, X. Escote, M. Aldea, and J. Clotet (2013)
Mol. Cell. Biol. 33, 1273-1284
   Abstract »    Full Text »    PDF »
New Horizons in Cellular Regulation by Inositol Polyphosphates: Insights from the Pancreatic {beta}-Cell.
C. J. Barker and P.-O. Berggren (2013)
Pharmacol. Rev. 65, 641-669
   Abstract »    Full Text »    PDF »
Inositol Pyrophosphates Modulate S Phase Progression after Pheromone-induced Arrest in Saccharomyces cerevisiae.
H. Banfic, A. Bedalov, J. D. York, and D. Visnjic (2013)
J. Biol. Chem. 288, 1717-1725
   Abstract »    Full Text »    PDF »
Synaptic Polarity Depends on Phosphatidylinositol Signaling Regulated by myo-Inositol Monophosphatase in Caenorhabditis elegans.
T. Kimata, Y. Tanizawa, Y. Can, S. Ikeda, A. Kuhara, and I. Mori (2012)
Genetics 191, 509-521
   Abstract »    Full Text »    PDF »
Regulation of Amino Acid, Nucleotide, and Phosphate Metabolism in Saccharomyces cerevisiae.
P. O. Ljungdahl and B. Daignan-Fornier (2012)
Genetics 190, 885-929
   Abstract »    Full Text »    PDF »
The Competitive Advantage of a Dual-Transporter System.
S. Levy, M. Kafri, M. Carmi, and N. Barkai (2011)
Science 334, 1408-1412
   Abstract »    Full Text »    PDF »
Regulation of Manganese Antioxidants by Nutrient Sensing Pathways in Saccharomyces cerevisiae.
A. R. Reddi and V. C. Culotta (2011)
Genetics 189, 1261-1270
   Abstract »    Full Text »    PDF »
Identification of an Evolutionarily Conserved Family of Inorganic Polyphosphate Endopolyphosphatases.
A. Lonetti, Z. Szijgyarto, D. Bosch, O. Loss, C. Azevedo, and A. Saiardi (2011)
J. Biol. Chem. 286, 31966-31974
   Abstract »    Full Text »    PDF »
Inositol Pyrophosphates as Mammalian Cell Signals.
A. Chakraborty, S. Kim, and S. H. Snyder (2011)
Science Signaling 4, re1
   Abstract »    Full Text »    PDF »
Phosphate-responsive Signaling Pathway Is a Novel Component of NAD+ Metabolism in Saccharomyces cerevisiae.
S.-P. Lu and S.-J. Lin (2011)
J. Biol. Chem. 286, 14271-14281
   Abstract »    Full Text »    PDF »
Casein kinase-2 mediates cell survival through phosphorylation and degradation of inositol hexakisphosphate kinase-2.
A. Chakraborty, J. K. Werner Jr., M. A. Koldobskiy, A. K. Mustafa, K. R. Juluri, J. Pietropaoli, A. M. Snowman, and S. H. Snyder (2011)
PNAS 108, 2205-2209
   Abstract »    Full Text »    PDF »
Systematic Screen of Schizosaccharomyces pombe Deletion Collection Uncovers Parallel Evolution of the Phosphate Signal Transduction Pathway in Yeasts.
T. C. Henry, J. E. Power, C. L. Kerwin, A. Mohammed, J. S. Weissman, D. M. Cameron, and D. D. Wykoff (2011)
Eukaryot. Cell 10, 198-206
   Abstract »    Full Text »    PDF »
p53-mediated apoptosis requires inositol hexakisphosphate kinase-2.
M. A. Koldobskiy, A. Chakraborty, J. K. Werner Jr., A. M. Snowman, K. R. Juluri, M. S. Vandiver, S. Kim, S. Heletz, and S. H. Snyder (2010)
PNAS 107, 20947-20951
   Abstract »    Full Text »    PDF »
Discovery of Mutations in Saccharomyces cerevisiae by Pooled Linkage Analysis and Whole-Genome Sequencing.
S. R. Birkeland, N. Jin, A. C. Ozdemir, R. H. Lyons Jr., L. S. Weisman, and T. E. Wilson (2010)
Genetics 186, 1127-1137
   Abstract »    Full Text »    PDF »
Asp1, a Conserved 1/3 Inositol Polyphosphate Kinase, Regulates the Dimorphic Switch in Schizosaccharomyces pombe.
J. Pohlmann and U. Fleig (2010)
Mol. Cell. Biol. 30, 4535-4547
   Abstract »    Full Text »    PDF »
Probing in vivo Mn2+ speciation and oxidative stress resistance in yeast cells with electron-nuclear double resonance spectroscopy.
R. L. McNaughton, A. R. Reddi, M. H. S. Clement, A. Sharma, K. Barnese, L. Rosenfeld, E. B. Gralla, J. S. Valentine, V. C. Culotta, and B. M. Hoffman (2010)
PNAS 107, 15335-15339
   Abstract »    Full Text »    PDF »
The Arabidopsis ATP-binding Cassette Protein AtMRP5/AtABCC5 Is a High Affinity Inositol Hexakisphosphate Transporter Involved in Guard Cell Signaling and Phytate Storage.
R. Nagy, H. Grob, B. Weder, P. Green, M. Klein, A. Frelet-Barrand, J. K. Schjoerring, C. Brearley, and E. Martinoia (2009)
J. Biol. Chem. 284, 33614-33622
   Abstract »    Full Text »    PDF »
The SPX domain of the yeast low-affinity phosphate transporter Pho90 regulates transport activity.
H. C. Hurlimann, B. Pinson, M. Stadler-Waibel, S. C. Zeeman, and F. M. Freimoser (2009)
EMBO Rep. 10, 1003-1008
   Abstract »    Full Text »    PDF »
Diphosphoinositol Polyphosphates: Metabolic Messengers?.
S. B. Shears (2009)
Mol. Pharmacol. 76, 236-252
   Abstract »    Full Text »    PDF »
Metabolic intermediates selectively stimulate transcription factor interaction and modulate phosphate and purine pathways.
B. Pinson, S. Vaur, I. Sagot, F. Coulpier, S. Lemoine, and B. Daignan-Fornier (2009)
Genes & Dev. 23, 1399-1407
   Abstract »    Full Text »    PDF »
Characterization of a Selective Inhibitor of Inositol Hexakisphosphate Kinases: USE IN DEFINING BIOLOGICAL ROLES AND METABOLIC RELATIONSHIPS OF INOSITOL PYROPHOSPHATES.
U. Padmanabhan, D. E. Dollins, P. C. Fridy, J. D. York, and C. P. Downes (2009)
J. Biol. Chem. 284, 10571-10582
   Abstract »    Full Text »    PDF »
Molecular regulators of phosphate homeostasis in plants.
W.-Y. Lin, S.-I Lin, and T.-J. Chiou (2009)
J. Exp. Bot. 60, 1427-1438
   Abstract »    Full Text »    PDF »
Dual Functions for the Schizosaccharomyces pombe Inositol Kinase Ipk1 in Nuclear mRNA Export and Polarized Cell Growth.
B. Sarmah and S. R. Wente (2009)
Eukaryot. Cell 8, 134-146
   Abstract »    Full Text »    PDF »
Structural Analysis and Detection of Biological Inositol Pyrophosphates Reveal That the Family of VIP/Diphosphoinositol Pentakisphosphate Kinases Are 1/3-Kinases.
H. Lin, P. C. Fridy, A. A. Ribeiro, J. H. Choi, D. K. Barma, G. Vogel, J. R. Falck, S. B. Shears, J. D. York, and G. W. Mayr (2009)
J. Biol. Chem. 284, 1863-1872
   Abstract »    Full Text »    PDF »
Regulation of Telomere Length by Fatty Acid Elongase 3 in Yeast: INVOLVEMENT OF INOSITOL PHOSPHATE METABOLISM AND Ku70/80 FUNCTION.
S. Ponnusamy, N. L. Alderson, H. Hama, J. Bielawski, J. C. Jiang, R. Bhandari, S. H. Snyder, S. M. Jazwinski, and B. Ogretmen (2008)
J. Biol. Chem. 283, 27514-27524
   Abstract »    Full Text »    PDF »
Cellular Energetic Status Supervises the Synthesis of Bis-Diphosphoinositol Tetrakisphosphate Independently of AMP-Activated Protein Kinase.
K. Choi, E. Mollapour, J. H. Choi, and S. B. Shears (2008)
Mol. Pharmacol. 74, 527-536
   Abstract »    Full Text »    PDF »
Saccharomyces cerevisiae Phospholipase C Regulates Transcription of Msn2p-Dependent Stress-Responsive Genes.
A. Demczuk, N. Guha, P. H. Nguyen, P. Desai, J. Chang, K. Guzinska, J. Rollins, C. C. Ghosh, L. Goodwin, and A. Vancura (2008)
Eukaryot. Cell 7, 967-979
   Abstract »    Full Text »    PDF »
The Nucleolus Exhibits an Osmotically Regulated Gatekeeping Activity That Controls the Spatial Dynamics and Functions of Nucleolin.
L. Yang, J. M. Reece, J. Cho, C. D. Bortner, and S. B. Shears (2008)
J. Biol. Chem. 283, 11823-11831
   Abstract »    Full Text »    PDF »
Gene deletion of inositol hexakisphosphate kinase 1 reveals inositol pyrophosphate regulation of insulin secretion, growth, and spermiogenesis.
R. Bhandari, K. R. Juluri, A. C. Resnick, and S. H. Snyder (2008)
PNAS 105, 2349-2353
   Abstract »    Full Text »    PDF »
HSP90 regulates cell survival via inositol hexakisphosphate kinase-2.
A. Chakraborty, M. A. Koldobskiy, K. M. Sixt, K. R. Juluri, A. K. Mustafa, A. M. Snowman, D. B. van Rossum, R. L. Patterson, and S. H. Snyder (2008)
PNAS 105, 1134-1139
   Abstract »    Full Text »    PDF »
A Discrete Signaling Function for an Inositol Pyrophosphate.
P. W. Majerus (2007)
Sci. STKE 2007, pe72
   Abstract »    Full Text »    PDF »
Requirement of Inositol Pyrophosphates for Full Exocytotic Capacity in Pancreatic {beta} Cells.
C. Illies, J. Gromada, R. Fiume, B. Leibiger, J. Yu, K. Juhl, S.-N. Yang, D. K. Barma, J. R. Falck, A. Saiardi, et al. (2007)
Science 318, 1299-1302
   Abstract »    Full Text »    PDF »
Cloning and Characterization of Two Human VIP1-like Inositol Hexakisphosphate and Diphosphoinositol Pentakisphosphate Kinases.
P. C. Fridy, J. C. Otto, D. E. Dollins, and J. D. York (2007)
J. Biol. Chem. 282, 30754-30762
   Abstract »    Full Text »    PDF »
Purification, Sequencing, and Molecular Identification of a Mammalian PP-InsP5 Kinase That Is Activated When Cells Are Exposed to Hyperosmotic Stress.
J. H. Choi, J. Williams, J. Cho, J. R. Falck, and S. B. Shears (2007)
J. Biol. Chem. 282, 30763-30775
   Abstract »    Full Text »    PDF »
Alterations in an inositol phosphate code through synergistic activation of a G protein and inositol phosphate kinases.
J. C. Otto, P. Kelly, S.-T. Chiou, and J. D. York (2007)
PNAS 104, 15653-15658
   Abstract »    Full Text »    PDF »
Protein pyrophosphorylation by inositol pyrophosphates is a posttranslational event.
R. Bhandari, A. Saiardi, Y. Ahmadibeni, A. M. Snowman, A. C. Resnick, T. Z. Kristiansen, H. Molina, A. Pandey, J. K. Werner Jr., K. R. Juluri, et al. (2007)
PNAS 104, 15305-15310
   Abstract »    Full Text »    PDF »
CELL SIGNALING: The Art of the Soluble.
R. Irvine (2007)
Science 316, 845-846
   Abstract »    Full Text »    PDF »
A Conserved Family of Enzymes That Phosphorylate Inositol Hexakisphosphate.
S. Mulugu, W. Bai, P. C. Fridy, R. J. Bastidas, J. C. Otto, D. E. Dollins, T. A. Haystead, A. A. Ribeiro, and J. D. York (2007)
Science 316, 106-109
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882