Autoinhibition of the Platelet-derived Growth Factor β-Receptor Tyrosine Kinase by Its C-terminal Tail

Federica Chiara,Subal Bishayee,Carl-Henrik Heldin,Jean-Baptiste Demoulin

doi:10.1074/jbc.m314070200

Federica Chiara, Subal Bishayee + Show 2 more

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https://doi.org/10.1074/jbc.m314070200

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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.

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platelet-derived growth factor (PDGF) participates in the development of certain tumors, as illustrated first by the observation that the simian sarcoma virus oncogene v-sis is functionally identical to PDGF-B [3, 4]
We investigated the role of the C-termi- causes a dramatic increase in its kinase activity, resulting in nal tail of the platelet-derived growth factor (PDGF) ␤-receptor in the control of the receptor kinase activity
Each receptor contains a tion of that residue has only a moderate effect on receptor large extracellular domain involved in growth factor binding phosphorylation [9], whereas the corresponding mutation in and an intracellular region that includes a split tyrosine kinase other tyrosine kinase receptors, such as the hepatocyte growth domain flanked by a juxtamembrane domain and a C-terminal factor receptor (c-Met) and insulin receptors, severely impairs tail

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PDGF participates in the development of certain tumors, as illustrated first by the observation that the simian sarcoma virus oncogene v-sis is functionally identical to PDGF-B [3, 4]. Using a panel of PDGF ␤-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 Vmax of the phosphotransfer reaction, in the absence of ligand, as compared with wild-type receptors.

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