Tau interacts with SHP2 in neuronal systems and in Alzheimer's disease brains

Abstract

Microtubule-associated protein tau, an integral component of neurofibrillary tangles, interacts with a variety of signaling molecules. Previously, our laboratory reported that nerve growth factor (NGF)induced MAPK activation in a PC12-derived cell line was potentiated by tau, with phosphorylation at T231 being required. Therefore, we sought to identify a signaling molecule involved in the NGF-induced Ras-MAPK pathway that interacted with phospho-T231-tau. Here, we report that the protein tyrosine phosphatase SHP2 (also known as PTPN11) interacted with tau, with phospho-T231 significantly enhancing the interaction. By using proximity ligation assays, we found that endogenous tau-SHP2 complexes were present in neuronal cells, where the number of tau-SHP2 complexes significantly increased when the cells were treated with NGF, with phosphorylation at T231 being required for the increase. The interaction did not require microtubule association, and an association between tau and activated SHP2 was also found. Tau-SHP2 complexes were also found in both primary mouse hippocampal cultures and adult mouse brain. Finally, SHP2 levels were upregulated in samples from patients with mild and severe Alzheimer's disease (AD), and the level of tau-SHP2 complexes were increased in AD patient samples. These findings strongly suggest a role for the tau-SHP2 interaction in NGF-stimulated neuronal development and in AD. This article has an associated First Person interview with the first author of the paper.

Tau: A Signaling Hub Protein

“…Tau phosphorylation at T231 potentiated NGF-induced activation of ERK1/2 kinases, whereas phosphorylation at S214 or the PHF1 site (S396/S404) inhibited this signaling (Leugers and Lee, 2010 ; Leugers et al, 2013 ). Additional work suggested that these effects might involve a direct, activating protein-protein interaction between tau and SHP2 (Kim et al, 2019 ). Tau and SHP2 interacted in pulldown assays and both proteins were identified as components of a larger protein complex using proximity ligation assays (Kim et al, 2019 ).…”

“…Additional work suggested that these effects might involve a direct, activating protein-protein interaction between tau and SHP2 (Kim et al, 2019 ). Tau and SHP2 interacted in pulldown assays and both proteins were identified as components of a larger protein complex using proximity ligation assays (Kim et al, 2019 ). Pseudophosphorylation at T231 in tau enhanced the interaction with SHP2 in cells compared to T231A tau (Kim et al, 2019 ).…”

“…Tau and SHP2 interacted in pulldown assays and both proteins were identified as components of a larger protein complex using proximity ligation assays (Kim et al, 2019 ). Pseudophosphorylation at T231 in tau enhanced the interaction with SHP2 in cells compared to T231A tau (Kim et al, 2019 ). Evidence from human tissue studies suggests tau-SHP2 interactions are increased in mild cognitive impairment and in AD brains when compared to non-demented control brains (Kim et al, 2019 ).…”

“…Pseudophosphorylation at T231 in tau enhanced the interaction with SHP2 in cells compared to T231A tau (Kim et al, 2019 ). Evidence from human tissue studies suggests tau-SHP2 interactions are increased in mild cognitive impairment and in AD brains when compared to non-demented control brains (Kim et al, 2019 ). Additionally, tau interacts with the SH3 domain of an SHP2-activator protein, Grb2, but whether SHP2 and Grb2 interact simultaneously with tau and the functional implications of these interactions are not yet well-defined (Reynolds et al, 2008 ).…”

Data-Driven Modeling of Knowledge Assemblies in Understanding Comorbidity Between Type 2 Diabetes Mellitus and Alzheimer’s Disease

“…The identification of two SNPs (i.e., rs1801270 and rs1059234) in CDKN1A positively correlated with NFT aggregation in AD patients [49]. The binding of protein tyrosine phosphatase non-receptor type 11 (PTPN11) and MAPT promotes neurogenesis by activating nerve growth factor [52]. Besides, matrix metallopeptidase 9 (MMP9) is also suggested to play a part in neurogenesis and other biological processes such as hypertension, demyelination, and inflammatory response [53,54].…”