Journal article
Regulation of carbamoyl phosphate synthetase by MAP kinase
Nature (London), Vol.403(6767), pp.328-332
01/20/2000
DOI: 10.1038/35002111
PMID: 10659854
Abstract
The de novo synthesis of pyrimidine nucleotides is required for mammalian cells to proliferate. The rate-limiting step in this pathway is catalysed by carbamoyl phosphate synthetase (CPS II), part of the multifunctional enzyme CAD1,2. Here we describe the regulation of CAD by the mitogen-activated protein (MAP) kinase cascade. When phosphorylated by MAP kinase in vitro or activated by epidermal growth factor in vivo , CAD lost its feedback inhibition (which is dependent on uridine triphosphate) and became more sensitive to activation (which depends upon phosphoribosyl pyrophosphate). Both these allosteric regulatory changes favour biosynthesis of pyrimidines for growth2. They were accompanied by increased epidermal growth factor-dependent phosphorylation of CAD in vivo and were prevented by inhibition of MAP kinase. Mutation of a consensus MAP kinase phosphorylation site abolished the changes in CAD allosteric regulation that were stimulated by growth factors. Finally, consistent with an effect of MAP kinase signalling on CPS II activity, epidermal growth factor increased cellular uridine triphosphate and this increase was reversed by inhibition of MAP kinase. Hence these studies may indicate a direct link between activation of the MAP kinase cascade and de novo biosynthesis of pyrimidine nucleotides.
Details
- Title: Subtitle
- Regulation of carbamoyl phosphate synthetase by MAP kinase
- Creators
- Lee M GravesHedeel I Guy - Wayne State UniversityPiotr KozlowskiMin HuangEduardo Lazarowski - University of North Carolina at Chapel HillR Marshall Pope - Medicine AdministrationMatthew A Collins - University of North Carolina at Chapel HillErik N Dahlstrand - University of North Carolina at Chapel HillH Shelton Earp III - University of North Carolina at Chapel HillDavid R Evans - Wayne State University
- Resource Type
- Journal article
- Publication Details
- Nature (London), Vol.403(6767), pp.328-332
- Publisher
- Nature Publishing Group
- DOI
- 10.1038/35002111
- PMID
- 10659854
- ISSN
- 0028-0836
- eISSN
- 1476-4687
- Language
- English
- Date published
- 01/20/2000
- Academic Unit
- Medicine Administration
- Record Identifier
- 9984627228602771
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