Differential regulation of protein tyrosine kinase signalling by Dock and the PTP61F variants

Lee F. Willoughby, Jan Manent, Kirsten Allan, Joo Han Lee, Marta Portela, Florian Wiede, Coral Warr, Tzu-Ching Meng, Tony Tiganis, Helena Elizabeth Richardson

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Tyrosine phosphorylation-dependent signalling is coordinated by the opposing actions of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). There is a growing list of adaptor proteins that interact with PTPs and facilitate the dephosphorylation of substrates. The extent to which any given adaptor confers selectivity for any given substrate in vivo remains unclear. Here we have taken advantage of Drosophila melanogaster as a model organism to explore the influence of the SH3/SH2 adaptor protein Dock on the abilities of the membrane (PTP61Fm)- and nuclear (PTP61Fn)-targeted variants of PTP61F (the Drosophila othologue of the mammalian enzymes PTP1B and TCPTP respectively) to repress PTK signalling pathways in vivo. PTP61Fn effectively repressed the eye overgrowth associated with activation of the epidermal growth factor receptor (EGFR), PTK, or the expression of the platelet-derived growth factor/vascular endothelial growth factor receptor (PVR) or insulin receptor (InR) PTKs. PTP61Fn repressed EGFR and PVR-induced mitogen-activated protein kinase signalling and attenuated PVR-induced STAT92E signalling. By contrast, PTP61Fm effectively repressed EGFR- and PVR-, but not InR-induced tissue overgrowth. Importantly, coexpression of Dock with PTP61F allowed for the efficient repression of the InR-induced eye overgrowth, but did not enhance the PTP61Fm-mediated inhibition of EGFR and PVR-induced signalling. Instead, Dock expression increased, and PTP61Fm coexpression further exacerbated the PVR-induced eye overgrowth. These results demonstrate that Dock selectively enhances the PTP61Fm-mediated attenuation of InR signalling and underscores the specificity of PTPs and the importance of adaptor proteins in regulating PTP function in vivo.

Original languageEnglish
Pages (from-to)2231-2250
Number of pages20
JournalFEBS Journal
Volume284
Issue number14
DOIs
Publication statusPublished - Jul 2017

Keywords

  • Drosophila
  • JAK/STAT
  • Protein tyrosine kinases
  • Protein tyrosine phosphatases
  • PTP61F

Cite this

Willoughby, L. F., Manent, J., Allan, K., Lee, J. H., Portela, M., Wiede, F., ... Richardson, H. E. (2017). Differential regulation of protein tyrosine kinase signalling by Dock and the PTP61F variants. FEBS Journal, 284(14), 2231-2250. https://doi.org/10.1111/febs.14118
Willoughby, Lee F. ; Manent, Jan ; Allan, Kirsten ; Lee, Joo Han ; Portela, Marta ; Wiede, Florian ; Warr, Coral ; Meng, Tzu-Ching ; Tiganis, Tony ; Richardson, Helena Elizabeth. / Differential regulation of protein tyrosine kinase signalling by Dock and the PTP61F variants. In: FEBS Journal. 2017 ; Vol. 284, No. 14. pp. 2231-2250.
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abstract = "Tyrosine phosphorylation-dependent signalling is coordinated by the opposing actions of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). There is a growing list of adaptor proteins that interact with PTPs and facilitate the dephosphorylation of substrates. The extent to which any given adaptor confers selectivity for any given substrate in vivo remains unclear. Here we have taken advantage of Drosophila melanogaster as a model organism to explore the influence of the SH3/SH2 adaptor protein Dock on the abilities of the membrane (PTP61Fm)- and nuclear (PTP61Fn)-targeted variants of PTP61F (the Drosophila othologue of the mammalian enzymes PTP1B and TCPTP respectively) to repress PTK signalling pathways in vivo. PTP61Fn effectively repressed the eye overgrowth associated with activation of the epidermal growth factor receptor (EGFR), PTK, or the expression of the platelet-derived growth factor/vascular endothelial growth factor receptor (PVR) or insulin receptor (InR) PTKs. PTP61Fn repressed EGFR and PVR-induced mitogen-activated protein kinase signalling and attenuated PVR-induced STAT92E signalling. By contrast, PTP61Fm effectively repressed EGFR- and PVR-, but not InR-induced tissue overgrowth. Importantly, coexpression of Dock with PTP61F allowed for the efficient repression of the InR-induced eye overgrowth, but did not enhance the PTP61Fm-mediated inhibition of EGFR and PVR-induced signalling. Instead, Dock expression increased, and PTP61Fm coexpression further exacerbated the PVR-induced eye overgrowth. These results demonstrate that Dock selectively enhances the PTP61Fm-mediated attenuation of InR signalling and underscores the specificity of PTPs and the importance of adaptor proteins in regulating PTP function in vivo.",
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Willoughby, LF, Manent, J, Allan, K, Lee, JH, Portela, M, Wiede, F, Warr, C, Meng, T-C, Tiganis, T & Richardson, HE 2017, 'Differential regulation of protein tyrosine kinase signalling by Dock and the PTP61F variants' FEBS Journal, vol. 284, no. 14, pp. 2231-2250. https://doi.org/10.1111/febs.14118

Differential regulation of protein tyrosine kinase signalling by Dock and the PTP61F variants. / Willoughby, Lee F.; Manent, Jan; Allan, Kirsten; Lee, Joo Han; Portela, Marta; Wiede, Florian; Warr, Coral; Meng, Tzu-Ching; Tiganis, Tony; Richardson, Helena Elizabeth.

In: FEBS Journal, Vol. 284, No. 14, 07.2017, p. 2231-2250.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Willoughby, Lee F.

AU - Manent, Jan

AU - Allan, Kirsten

AU - Lee, Joo Han

AU - Portela, Marta

AU - Wiede, Florian

AU - Warr, Coral

AU - Meng, Tzu-Ching

AU - Tiganis, Tony

AU - Richardson, Helena Elizabeth

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AB - Tyrosine phosphorylation-dependent signalling is coordinated by the opposing actions of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). There is a growing list of adaptor proteins that interact with PTPs and facilitate the dephosphorylation of substrates. The extent to which any given adaptor confers selectivity for any given substrate in vivo remains unclear. Here we have taken advantage of Drosophila melanogaster as a model organism to explore the influence of the SH3/SH2 adaptor protein Dock on the abilities of the membrane (PTP61Fm)- and nuclear (PTP61Fn)-targeted variants of PTP61F (the Drosophila othologue of the mammalian enzymes PTP1B and TCPTP respectively) to repress PTK signalling pathways in vivo. PTP61Fn effectively repressed the eye overgrowth associated with activation of the epidermal growth factor receptor (EGFR), PTK, or the expression of the platelet-derived growth factor/vascular endothelial growth factor receptor (PVR) or insulin receptor (InR) PTKs. PTP61Fn repressed EGFR and PVR-induced mitogen-activated protein kinase signalling and attenuated PVR-induced STAT92E signalling. By contrast, PTP61Fm effectively repressed EGFR- and PVR-, but not InR-induced tissue overgrowth. Importantly, coexpression of Dock with PTP61F allowed for the efficient repression of the InR-induced eye overgrowth, but did not enhance the PTP61Fm-mediated inhibition of EGFR and PVR-induced signalling. Instead, Dock expression increased, and PTP61Fm coexpression further exacerbated the PVR-induced eye overgrowth. These results demonstrate that Dock selectively enhances the PTP61Fm-mediated attenuation of InR signalling and underscores the specificity of PTPs and the importance of adaptor proteins in regulating PTP function in vivo.

KW - Drosophila

KW - JAK/STAT

KW - Protein tyrosine kinases

KW - Protein tyrosine phosphatases

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