Back to Search
Start Over
RET Functions as a Dual-Specificity Kinase that Requires Allosteric Inputs from Juxtamembrane Elements.
- Source :
-
Cell reports [Cell Rep] 2016 Dec 20; Vol. 17 (12), pp. 3319-3332. - Publication Year :
- 2016
-
Abstract
- Receptor tyrosine kinases exhibit a variety of activation mechanisms despite highly homologous catalytic domains. Such diversity arises through coupling of extracellular ligand-binding portions with highly variable intracellular sequences flanking the tyrosine kinase domain and specific patterns of autophosphorylation sites. Here, we show that the juxtamembrane (JM) segment enhances RET catalytic domain activity through Y687. This phospho-site is also required by the JM region to rescue an otherwise catalytically deficient RET activation-loop mutant lacking tyrosines. Structure-function analyses identified interactions between the JM hinge, αC helix, and an unconventional activation-loop serine phosphorylation site that engages the HRD motif and promotes phospho-tyrosine conformational accessibility and regulatory spine assembly. We demonstrate that this phospho-S909 arises from an intrinsic RET dual-specificity kinase activity and show that an equivalent serine is required for RET signaling in Drosophila. Our findings reveal dual-specificity and allosteric components for the mechanism of RET activation and signaling with direct implications for drug discovery.<br /> (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Allosteric Regulation genetics
Amino Acid Sequence genetics
Animals
Cell Membrane chemistry
Cell Membrane metabolism
Drosophila Proteins genetics
Drosophila melanogaster
Enzyme Activation genetics
Phosphorylation
Proto-Oncogene Proteins c-ret genetics
Receptor Protein-Tyrosine Kinases genetics
Serine metabolism
Signal Transduction genetics
Drosophila Proteins chemistry
Drosophila Proteins metabolism
Proto-Oncogene Proteins c-ret chemistry
Proto-Oncogene Proteins c-ret metabolism
Receptor Protein-Tyrosine Kinases chemistry
Structure-Activity Relationship
Subjects
Details
- Language :
- English
- ISSN :
- 2211-1247
- Volume :
- 17
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Cell reports
- Publication Type :
- Academic Journal
- Accession number :
- 28009299
- Full Text :
- https://doi.org/10.1016/j.celrep.2016.11.061