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

Zhong Yao; Katelyn Darowski; Nicole St-Denis; Victoria Wong; Fabian Offensperger; Annabel Villedieu; Shahreen Amin; Ramy Malty; Hiroyuki Aoki; Hongbo Guo; Yang Xu; Caterina Iorio; Max Kotlyar; Andrew Emili; Igor Jurisica; Benjamin G Neel; Mohan Babu; Anne-Claude Gingras; Igor Stagljar

doi:10.1016/j.molcel.2016.12.004

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

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

Authors

Zhong Yao¹, Katelyn Darowski¹, Nicole St-Denis², Victoria Wong¹, Fabian Offensperger¹, Annabel Villedieu¹, Shahreen Amin³, Ramy Malty³, Hiroyuki Aoki³, Hongbo Guo¹, Yang Xu⁴, Caterina Iorio⁴, Max Kotlyar⁴, Andrew Emili⁵, Igor Jurisica⁶, Benjamin G Neel⁷, Mohan Babu³, Anne-Claude Gingras⁸, Igor Stagljar⁹

Affiliations

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.

MeSH terms

Animals
Enzyme Activation
Epidermal Growth Factor / pharmacology
ErbB Receptors / agonists
ErbB Receptors / genetics
ErbB Receptors / metabolism*
HEK293 Cells
Humans
Mice
Mutation
Phosphorylation
Protein Interaction Mapping
Protein Interaction Maps*
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
Signal Transduction* / drug effects
Transfection
Two-Hybrid System Techniques
src-Family Kinases / genetics
src-Family Kinases / metabolism*

Substances

Epidermal Growth Factor
EGFR protein, human
ErbB Receptors
src-Family Kinases
PTPRA protein, human
PTPRB protein, human
PTPRH protein, human
Receptor-Like Protein Tyrosine Phosphatases, Class 3
Receptor-Like Protein Tyrosine Phosphatases, Class 4

Abstract

MeSH terms

Substances

Grants and funding