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Autoinhibition of the platelet-derived growth factor beta-receptor tyrosine kinase by its C-terminal tail
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
2004 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 279, no 19, 19732-19738 p.Article in journal (Refereed) Published
Abstract [en]

In this report, we investigated the role of the C-terminal tail of the platelet-derived growth factor (PDGF) beta-receptor in the control of the receptor kinase activity. Using a panel of PDGF beta-receptor mutants with progressive C-terminal truncations, we observed that deletion of the last 46 residues, which contain a proline- and glutamic acid-rich motif, increased the autoactivation velocity in vitro and the V(max) of the phosphotransfer reaction, in the absence of ligand, as compared with wild-type receptors. By contrast, the kinase activity of mutant and wild-type receptors that were pre-activated by treatment with PDGF was comparable. Using a conformation-sensitive antibody, we found that truncated receptors presented an active conformation even in the absence of PDGF. A soluble peptide containing the Pro/Glu-rich motif specifically inhibited the PDGF beta-receptor kinase activity. Whereas deletion of this motif was not enough to confer ligand-independent transforming ability to the receptor, it dramatically enhanced the effect of the weakly activating D850N mutation in a focus formation assay. These findings indicate that allosteric inhibition of the PDGF beta-receptor by its C-terminal tail is one of the mechanisms involved in keeping the receptor inactive in the absence of ligand.

Place, publisher, year, edition, pages
2004. Vol. 279, no 19, 19732-19738 p.
Keyword [en]
Amino Acid Motifs, Amino Acid Sequence, Animals, Blotting; Western, COS Cells, Dose-Response Relationship; Drug, Gene Deletion, Humans, Kinetics, Ligands, Models; Biological, Molecular Sequence Data, Mutagenesis; Site-Directed, Mutation, Peptides/chemistry, Protein Conformation, Protein Structure; Tertiary, Receptor; Platelet-Derived Growth Factor beta/chemistry/metabolism/*physiology, Research Support; Non-U.S. Gov't, Sequence Homology; Amino Acid, Time Factors, Transfection
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-72903DOI: 10.1074/jbc.M314070200PubMedID: 14996833OAI: oai:DiVA.org:uu-72903DiVA: diva2:100814
Available from: 2005-05-30 Created: 2005-05-30 Last updated: 2017-12-14Bibliographically approved

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Heldin, Carl-Henrik

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