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Mol Cell. 2017 Jan 19;65(2):347-360. doi: 10.1016/j.molcel.2016.12.004. Epub 2017 Jan 5.

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

Author information

1
Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
2
Lunenfeld-Tanenbaum Research Institute at Mount Sinai, Toronto, ON M5G 1X5, Canada.
3
Department of Biochemistry, University of Regina, Regina, SK S4S 0A2, Canada.
4
Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.
5
Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
6
Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada; Department of Computer Science, University of Toronto, Toronto, ON M5S 3G4, Canada; Institute of Neuroimmunology, Slovak Academy of Sciences, 845 10 Bratislava, Slovak Republic.
7
Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada; Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada.
8
Lunenfeld-Tanenbaum Research Institute at Mount Sinai, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
9
Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: igor.stagljar@utoronto.ca.

Abstract

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.

KEYWORDS:

MYTH; MaMTH; PTP; PTPRA; PTPRB; PTPRH; RTK; SRC; dephosphorylation; phosphatase

PMID:
28065597
PMCID:
PMC5663465
DOI:
10.1016/j.molcel.2016.12.004
[Indexed for MEDLINE]
Free PMC Article

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