A Global Analysis of the Receptor Tyrosine Kinase-Protein Phosphatase Interactome

Receptor tyrosine kinases (RTKs) and protein phosphatases comprise protein families that play crucial roles in cell signaling. We used two protein-protein interaction (PPI) approaches, the membrane yeast two-hybrid (MYTH) and the mammalian membrane two-hybrid (MaMTH), to map the PPIs between human R...

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Bibliographic Details
Published in:Molecular cell 2017-01, Vol.65 (2), p.347-360
Main Authors: Yao, Zhong, Darowski, Katelyn, St-Denis, Nicole, Wong, Victoria, Offensperger, Fabian, Villedieu, Annabel, Amin, Shahreen, Malty, Ramy, Aoki, Hiroyuki, Guo, Hongbo, Xu, Yang, Iorio, Caterina, Kotlyar, Max, Emili, Andrew, Jurisica, Igor, Neel, Benjamin G., Babu, Mohan, Gingras, Anne-Claude, Stagljar, Igor
Format: Article
Language:English
Subjects:
Animals
dephosphorylation
Enzyme Activation
Epidermal Growth Factor - pharmacology
ErbB Receptors - agonists
ErbB Receptors - genetics
ErbB Receptors - metabolism
HEK293 Cells
Humans
MaMTH
Mice
Mutation
MYTH
phosphatase
Phosphorylation
Protein Interaction Mapping
Protein Interaction Maps
PTP
PTPRA
PTPRB
PTPRH
Receptor-Like Protein Tyrosine Phosphatases, Class 3 - genetics
Receptor-Like Protein Tyrosine Phosphatases, Class 3 - metabolism
Receptor-Like Protein Tyrosine Phosphatases, Class 4 - genetics
Receptor-Like Protein Tyrosine Phosphatases, Class 4 - metabolism
Reproducibility of Results
RTK
Signal Transduction - drug effects
SRC
src-Family Kinases - genetics
src-Family Kinases - metabolism
Transfection
Two-Hybrid System Techniques
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Summary:Receptor tyrosine kinases (RTKs) and protein phosphatases comprise protein families that play crucial roles in cell signaling. We used two protein-protein interaction (PPI) approaches, the membrane yeast two-hybrid (MYTH) and the mammalian membrane two-hybrid (MaMTH), to map the PPIs between human RTKs and phosphatases. The resulting RTK-phosphatase interactome reveals a considerable number of previously unidentified interactions and suggests specific roles for different phosphatase families. Additionally, the differential PPIs of some protein tyrosine phosphatases (PTPs) and their mutants suggest diverse mechanisms of these PTPs in the regulation of RTK signaling. We further found that PTPRH and PTPRB directly dephosphorylate EGFR and repress its downstream signaling. By contrast, PTPRA plays a dual role in EGFR signaling: besides facilitating EGFR dephosphorylation, it enhances downstream ERK signaling by activating SRC. This comprehensive RTK-phosphatase interactome study provides a broad and deep view of RTK signaling. [Display omitted] •MYTH and MaMTH screens identified numerous RTK-phosphatase interactions•Diversity of RTK/PTP interaction suggests different modes of their functions•PTPRH and PTPRB inhibit EGFR signaling through direct dephosphorylation•PTPRA specifically potentiates EGFR interaction through activating SRC Using MYTH and MaMTH protein interaction assays, Yao et al. performed comprehensive RTK-phosphatase screens and identified diverse interactions. Among many of these, they show that PTPRH and PTPRB inhibit EGFR signaling by directly dephosphorylating EGFR. By contrast, PTPRA potentiates EGFR signaling through activatory dephosphorylation of SRC and facilitating EGFR/SRC association.
ISSN:1097-2765
1097-4164
DOI:10.1016/j.molcel.2016.12.004