Skip to main content
SpringerLink
Log in

CoA Synthase is phosphorylated on tyrosines in mammalian cells, interacts with and is dephosphorylated by Shp2PTP

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

CoA Synthase (CoASy, 4′-phosphopantetheine adenylyltransferase/dephospho-CoA kinase) mediates two final stages of de novo coenzyme A (CoA) biosynthesis in higher eukaryotes. Unfortunately very little is known about regulation of this important metabolic pathway. In this study, we demonstrate that CoASy interacts in vitro with Src homology-2 (SH2) domains of a number of signaling proteins, including Src homology-2 domains containing protein tyrosine phosphatase (Shp2PTP). Complexes between CoASy and Shp2PTP exist in vivo in mammalian cells and this interaction is regulated in a growth-factor-dependent manner. We have also demonstrated that endogenous CoASy is phosphorylated on tyrosine residues in vivo, and that cytoplasmic protein tyrosine kinases can mediate this phosphorylation in vitro and in vivo. Importantly, Shp2PTP-mediated CoASy in vitro dephosphorylation leads to an increase in CoASy enzymatic phosphopantetheine adenylyltransferase (PPAT) activity. We therefore argue that CoASy is a novel potential substrate of Shp2PTP and phosphorylation of CoASy at tyrosine residue(s) could represent unrecognized before mechanism of modulation intracellular CoA level in response to hormonal and (or) other extracellular stimuli.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. Zhyvoloup A, Nemazanyy I, Panasyuk G, Valovka T, Fenton T, Rebholz H, Wang ML, Foxon R, Lyzogubov V, Usenko V, Kyyamova R, Gorbenko O, Matsuka G, Filonenko V, Gout IT (2003) Subcellular localization and regulation of coenzyme A synthase. J Biol Chem 278:50316–50321

    Article  CAS  PubMed  Google Scholar 

  2. Daugherty M, Polanuyer B, Farrell M, Scholle M, Lykidis A, de Crécy-Lagard V, Osterman A (2002) Complete reconstitution of the human coenzyme A biosynthetic pathway via comparative genomics. J Biol Chem 277:21431–21439

    Article  CAS  PubMed  Google Scholar 

  3. Abiko Y (1975) Methabolism of coenzyme A. In: Greenberg D (ed) Metabolic pathways. Academic Press, New York, pp 25–50

    Google Scholar 

  4. Leonardi R, Zhang YM, Rock CO, Jackowski S (2005) Coenzyme A: back in action. Prog Lipid Res 44:125–153

    Article  CAS  PubMed  Google Scholar 

  5. Black PN, Faergeman NJ, DiRusso CC (2000) Long-chain acyl-CoA-dependent regulation of gene expression in bacteria, yeast and mammals. J Nutr 130:305S–309S

    CAS  PubMed  Google Scholar 

  6. Takahashi H, McCaffery JM, Irizarry RA, Boeke JD (2006) Nucleocytosolic acetyl-coenzyme A synthetase is required for histone acetylation and global transcription. Mol Cell 23:207–217

    Article  CAS  PubMed  Google Scholar 

  7. Bosveld F, Rana A, Van der Wouden PE, Lemstra W, Ritsema M, Kampinga HH, Sibon OC (2008) De novo CoA biosynthesis is required to maintain DNA integrity during development of the Drosophila nervous system. Hum Mol Genet 17:2058–2069

    Article  CAS  PubMed  Google Scholar 

  8. Resh MD (1996) Regulation of cellular signalling by fatty acid acylation and prenylation of signal transduction proteins. Cell Signal 8:403–412

    Article  CAS  PubMed  Google Scholar 

  9. Linder ME, Deschenes RJ (2007) Palmitoylation: policing protein stability and traffic. Nat Rev Mol Cell Biol 87:4–884

    Google Scholar 

  10. Pfanner N, Orci L, Glick BS, Amherdt M, Arden SR, Malhotra V, Rothman JE (1989) Fatty acyl-coenzyme A is required for budding of transport vesicles from Golgi cisternae. Cell 59:95–102

    Article  CAS  PubMed  Google Scholar 

  11. Rock CO, Calder RB, Karim MA, Jackowski S (2002) The murine pantothenate kinase (Pank1) gene encodes two differentially regulated pantothenate kinase isozymes. Gene 291:35–43

    Article  CAS  PubMed  Google Scholar 

  12. Leonardi R, Rock CO, Jackowski S, Zhang YM (2007) Activation of human mitochondrial pantothenate kinase 2 by palmitoylcarnitine. Proc Natl Acad Sci USA 104:1494–1499

    Article  CAS  PubMed  Google Scholar 

  13. Ramaswamy G, Karim MA, Murti KG, Jackowski S (2004) PPARalpha controls the intracellular coenzyme A concentration via regulation of PANK1alpha gene expression. J Lipid Res 45:17–31

    Article  CAS  PubMed  Google Scholar 

  14. Rock CO, Calder RB, Karim MA, Jackowski S (2000) Pantothenate kinase regulation of the intracellular concentration of coenzyme A. J Biol Chem 275:1377–1383

    Article  CAS  PubMed  Google Scholar 

  15. Xue Y, Ren J, Gao X, Jin C, Wen L, Yao X (2008) GPS 2.0, a tool to predict kinase-specific phosphorylation sites in hierarchy. Mol Cell Proteomics 7:1598–1608

    Article  CAS  PubMed  Google Scholar 

  16. Obenauer JC, Cantley LC, Yaffe MB (2003) Scansite 2.0: proteome-wide prediction of cell signalling interactions using short sequence motifs. Nucleic Acids Res 31:3635–3641

    Article  CAS  PubMed  Google Scholar 

  17. Gout IT, Dhand R, Hiles ID, Fry M, Panayotou G, Das P, Truong O, Totty N, Hsuan J, Booker G, Campbell I, Waterfield M (1993) The GTPase dynamin binds to and is activated by a subset of SH3 domains. Cell 75:25–36

    CAS  PubMed  Google Scholar 

  18. Nemazanyy I, Panasyuk G, Zhyvoloup A, Panayotou G, Gout IT, Filonenko V (2004) Specific interaction between S6K1 and CoA Synthase: a potential link between the mTOR/S6K pathway. CoA biosynthesis and energy metabolism. FEBS Lett 578:357–362

    Article  CAS  PubMed  Google Scholar 

  19. Aghajanian S, Worrall DM (2002) Identification and characterization of the gene encoding the human phosphopantetheine adenylyltransferase and dephospho-CoA kinase bifunctional enzyme (CoA synthase). Biochem J 365:13–18

    CAS  PubMed  Google Scholar 

  20. Neel BG, Gu H, Pao L (2003) The ‘Shp’ing news: SH2 domain-containing tyrosine phosphatases in cell signalling. Trends Biochem Sci 28:284–293

    Article  CAS  PubMed  Google Scholar 

  21. Bone H, Dechert U, Jirik F, Schrader JW, Welham MJ (1997) SHP1 and SHP2 protein-tyrosine phosphatases associate with betac after interleukin-3-induced receptor tyrosine phosphorylation. Identification of potential binding sites and substrates. J Biol Chem 272:14470–14476

    Article  CAS  PubMed  Google Scholar 

  22. Philosof-Oppenheimer R, Hampe CS, Schlessinger K, Fridkin M, Pecht I (2000) An immunoreceptor tyrosine-based inhibitory motif, with serine at site Y-2, binds SH2-domain-containing phosphatases. Eur J Biochem 267:703–711

    Article  CAS  PubMed  Google Scholar 

  23. Smith CM, Cano ML, Potyraj J (1978) The relationship between metabolic state, total CoA content of rat liver, heart. J Nutr 108:854–862

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Ivan Nemazanyy was supported by Wood-Whelan Research Fellowship, Oksana Breus was supported by EMBO Short-term fellowship. We thank Dr. Zamal Ahmed for providing us with Shp2PTP–GST recombinant protein and Nadeem Shaikh for critical reading of the manuscript and helpful suggestions.

Author information

Authors and Affiliations

  1. Department of Cell Signaling, Institute of Molecular Biology and Genetics NAS of Ukraine, 150 Zabolotnogo Street, 03680, Kyiv, Ukraine

    Oksana Breus, Ganna Panasyuk, Ivan T. Gout, Valeriy Filonenko & Ivan Nemazanyy

  2. Research Department of Structural and Molecular Biology, University College London, London, UK

    Ganna Panasyuk & Ivan T. Gout

Authors
  1. Oksana Breus
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ganna Panasyuk
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ivan T. Gout
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Valeriy Filonenko
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ivan Nemazanyy
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Valeriy Filonenko.

Additional information

Oksana Breus and Ganna Panasyuk contributed equally to this article.

Electronic supplementary material

Below is the link to the electronic supplementary material.

(PPT 98 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Breus, O., Panasyuk, G., Gout, I.T. et al. CoA Synthase is phosphorylated on tyrosines in mammalian cells, interacts with and is dephosphorylated by Shp2PTP. Mol Cell Biochem 335, 195–202 (2010). https://doi.org/10.1007/s11010-009-0255-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-009-0255-6

Keywords

Search

Navigation