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

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.

The Genomic Architecture of Adaptation to Larval Malnutrition Points to a Trade-off with Adult Starvation Resistance in Drosophila

“…Also associated with candidate SNPs are key members of insulin receptor signaling, including foxo , a major transcription factor mediating transcriptomic response to reduced insulin signaling ( Alic et al. 2011 ), dock , which is a negative regulator of insulin signaling ( Willoughby et al. 2017 ), and the fat-body expressed ilp6 , which regulates metabolic response to nutrient shortage ( Chatterjee et al.…”

The genomic architecture of adaptation to larval malnutrition points to a trade-off with adult starvation resistance inDrosophila

“…Three transcription factors that play a key role in triggering metamorphosis in response to ecdysone ( Eip75B, Kr-h1 and fkh ) are likewise associated with candidate SNPs. Also associated with candidate SNPs are key members of insulin receptor signaling, including foxo , a major transcription factor mediating transcriptomic response to reduced insulin signaling (Alic et al 2011), dock , which is a negative regulator of insulin signaling (Willoughby et al 2017), and the fat-body expressed ilp6 , which regulates metabolic response to nutrient shortage (Chatterjee et al 2014). Interestingly - given the context of chronic nutrient shortage - we found no indication of the nutrient-sensing TOR signaling to have been targeted; none of the 62 genes in the GO term “TOR signaling” was associated with a candidate SNP.…”

PTP61F Mediates Cell Competition and Mitigates Tumorigenesis

“…Therefore, we reasoned that PTPs might play an unappreciated role in cell competition. We selected the Drosophila tyrosine phosphatase protein tyrosine phosphatase 61F ( Ptp61F ) as a candidate, as it has been shown to negatively regulate EGFR-RAS–MAPK and JAK–STAT signalling [ 27 ].…”

“…Our data thus far have demonstrated a new role for PTP61F as contributing to polarity-impaired cell competition. Previous studies have shown that PTP61F can attenuate JAK–STAT signalling in Drosophila [ 24 , 25 , 26 , 27 , 52 ], but whether PTP61F regulates JAK–STAT signalling in the context of cell competition is unclear. Moreover, although JAK–STAT signalling is known to play a role in the wild-type winner cells during polarity-impaired cell competition [ 53 ], it is unclear whether JAK–STAT signalling has a role within the polarity-impaired loser cells.…”

“…As in mammals, PTPs in Drosophila belong to either the transmembrane receptor or non-receptor subtypes [ 21 ]. The Drosophila non-receptor protein tyrosine phosphatase 61F ( Ptp61F ) functions as a negative regulator in a number of highly conserved signalling pathways, including the JAK–STAT pathway [ 24 , 25 , 26 , 27 ], the Insulin-like Receptor (INR) pathway [ 24 , 27 , 28 , 29 ], the EGFR- pathway [ 27 , 28 ], and the platelet-derived growth factor (PDGF)- and vascular endothelial growth factor (VEGF)-receptor-related (PVR) pathway [ 27 ]. PTP61F has two mammalian orthologues, PTP1B (encoded by PTPN1 ) and TCPTP (encoded by PTPN2 ), which share 74% catalytic domain sequence identity and 86% similarity (reviewed in [ 30 , 31 ]).…”