title: A Global Analysis of the Receptor Tyrosine Kinase-Protein Phosphatase Interactome.
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.
authors.affiliation: Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Yao
authors.affiliation: Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
authors.forename: Katelyn
authors.initials: K
authors.lastname: Darowski
authors.affiliation: Lunenfeld-Tanenbaum Research Institute at Mount Sinai, Toronto, ON M5G 1X5, Canada.
authors.forename: Nicole
authors.initials: N
authors.lastname: St-Denis
authors.affiliation: Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
authors.forename: Victoria
authors.initials: V
authors.lastname: Wong
authors.affiliation: Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
authors.forename: Fabian
authors.initials: F
authors.lastname: Offensperger
authors.affiliation: Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
authors.forename: Annabel
authors.initials: A
authors.lastname: Villedieu
authors.affiliation: Department of Biochemistry, University of Regina, Regina, SK S4S 0A2, Canada.
authors.forename: Shahreen
authors.initials: S
authors.lastname: Amin
authors.affiliation: Department of Biochemistry, University of Regina, Regina, SK S4S 0A2, Canada.
authors.forename: Ramy
authors.initials: R
authors.lastname: Malty
authors.affiliation: Department of Biochemistry, University of Regina, Regina, SK S4S 0A2, Canada.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aoki
authors.affiliation: Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Guo
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.
authors.forename: Caterina
authors.initials: C
authors.lastname: Iorio
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.
authors.forename: Max
authors.initials: M
authors.lastname: Kotlyar
authors.affiliation: Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Emili
authors.affiliation: 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.
authors.forename: Igor
authors.initials: I
authors.lastname: Jurisica
authors.affiliation: 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.
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Neel
authors.affiliation: Department of Biochemistry, University of Regina, Regina, SK S4S 0A2, Canada.
authors.forename: Mohan
authors.initials: M
authors.lastname: Babu
authors.affiliation: Lunenfeld-Tanenbaum Research Institute at Mount Sinai, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Anne-Claude
authors.initials: AC
authors.lastname: Gingras
authors.affiliation: 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.
authors.forename: Igor
authors.initials: I
authors.lastname: Stagljar
mesh_terms: D000818:Animals; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D009154:Mutation; D010766:Phosphorylation; D025941:Protein Interaction Mapping; D060066:Protein Interaction Maps; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3 / Q000235:genetics / Q000378:metabolism; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4 / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D020798:Two-Hybrid System Techniques; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D004815:Epidermal Growth Factor; C512478:EGFR protein, human; D066246:ErbB Receptors; D019061:src-Family Kinases; C516841:PTPRA protein, human; C516886:PTPRB protein, human; C431695:PTPRH protein, human; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4
keywords: MYTH; MaMTH; PTP; PTPRA; PTPRB; PTPRH; RTK; SRC; dephosphorylation; phosphatase