Differential regulation of protein tyrosine kinase signalling by Dock and the PTP61F variants. (30th June 2017)

• Record Type: Journal Article
• Authors: Willoughby, Lee F.; Manent, Jan; Allan, Kirsten; Lee, Han; Portela, Marta; Wiede, Florian; Warr, Coral; Meng, Tzu‐Ching; Tiganis, Tony; Richardson, Helena E.
• Is Part Of: FEBS journal. Volume 284:Number 14(2017)
• Page Start: 2231
• Page End: 2250
• Publication Date: 2017-06-30
• Subjects: Drosophila -- JAK/STAT -- protein tyrosine kinases -- protein tyrosine phosphatases -- PTP61F; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pathology, Molecular -- Periodicals; 572
• DOI: 10.1111/febs.14118
• Languages: English
• ISSNs: 1742-464X

Abstract

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 . Abstract : The protein tyrosine phosphatase, PTP61F, has two isoforms, PTP61Fm, which is membrane‐associated, and PTP61Fn, which is ubiquitously localised. In InR signalling, PTP61Fm requires the adaptor Dock to dephosphorylate and restrain InR activation, while PTP61Fn acts in a Dock‐independent manner. In EGFR and PVR signalling, PTP61Fn and PTP61Fm act independently of Dock to dephosphorylate and suppress receptor tyrosine kinase activity