TPN12 in controlling TrkB receptor proximal signaling events. This effect 10 Phosphatases Modulating Neurite Outgrowth of phosphorylation of TrkA and TrkC will also need to be considered. Interestingly, PTPN12 knockdown does not affect neurite outgrowth in absence of BDNF in SH-SY5Y cells, but does so in TrkB-SH-SY5Y cells. This may indicate that PTPN12 might modulate TrkB phosphorylation only when TrkB is itself activated; mechanisms responsible could include altered TrkB or PTPN12 localization, or modulation of PTPN12 catalytic activity in response to BDNF/TrkB activation. The phosphorylated Y816 CAL 101 biological activity residue in TrkB acts as a PLCc binding site, whereas 11259531 phosphorylation of another residue, Y515, is associated with Shc docking. The literature indicates that it is not possible to cleanly assign ERK activation to one site: there appear to be Y515/Shc-independent pathways to ERK activation, and the Y816/PLC-c-binding site can contribute to ERK activation by Trks. We have also observed statistically significant effects of PTPN12 knockdown on phosphorylation of the Y515 residue, a docking site for Shc. Thus, a causal link between PTPN12 knockdown-induced TrkB hyperphosphorylation and ERK hyperactivation seemed plausible. To investigate the contribution of TrkB hyperphosphorylation to the pERK1/2 activation associated with PTPN12 knockdown, we used the Trk inhibitor K252a. K252a treatment reduced the PTPN12 knockdown-induced increase in pERK1/2 by only 50%, suggesting that ERK activation following PTPN12 knockdown is only partly due to TrkB hyperactivation. The presence of hyperphosphorylated p130cas and FAK, associated with increased integrin responsiveness, might account for the remaining part of the elevated ERK phosphorylation following PTPN12 knockdown. At any rate 26836578 it may be exceedingly difficult, and of limited utility, to try and further disentangle both processes, as neuronal FAK and Src are integration points between growth factor and integrin signaling, with activation of both pathways having synergistic effects on neurite outgrowth. Outlook BDNF participates in regenerative processes, and decreased BDNF function is associated with neurodegeneration, cognitive decline, and psychiatric disorders. Our study reveals the extent of phosphatome regulation of BDNF responsiveness. Phosphatases that negatively control BDNF sensitivity may have promise as pharmacological targets to potentiate the effect of limiting amounts of endogenous factor. While the diversity in surface structure properties among PTPs might augur well for development of selective PTP inhibitors, and progress has been made, substantial hurdles remain to be overcome. Strikingly, while we identify PTPN12 as a novel negative regulator of BDNF-receptor activity, we observe that such “classical”PTPs only play a limited role in phosphatase control of this tyrosine kinase-mediated response. This prompts a comprehensive view of phosphatase control, with multiple categories of evolutionarily unrelated phosphatase families having converged to orchestrate a biological response. Our study thus reveals the breadth of the spectrum of target families that could potentially be exploited to modulate BDNF signaling to therapeutic effect. of PTPN12 on TrkB activation predominantly appears at nonsaturating levels of exogenous BDNF. One possibility is that PTPN12 directly dephosphorylates TrkB, similarly to the ability of RPTPf and RPTPs to dephosphorylate TrkA, and thereby attenuate NGF-induced E

Kolmogorov-Smirnov, Wilcoxon signed rank test and Spearman correlation were used

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