DOI

10.17077/etd.s971cyj6

Document Type

Dissertation

Date of Degree

Spring 2017

Degree Name

PhD (Doctor of Philosophy)

Degree In

Molecular and Cell Biology

First Advisor

Lee, Gloria

First Committee Member

Koland, John

Second Committee Member

DeMali, Kris

Third Committee Member

McNamara, James

Fourth Committee Member

Prahlad, Veena

Abstract

The microtubule-associated protein tau normally functions to bind to and stabilize microtubules. However, evidence now indicates that tau may also play a critical role in signaling pathways linked to neuronal development and neurodegeneration. The tau association with numerous signaling proteins such as tyrosine kinases, adaptor proteins, and scaffold proteins support this hypothesis. Phospho-Y18 tau was previously found in Alzheimer’s disease (AD) brain. Interestingly, this phosphorylation appeared to be regulated during neurodegeneration possibly by a tyrosine phosphatase(s). Identifying a candidate phosphatase, our lab found the association between tau and SHP2 in a neuronal cell line and dephosphorylation of phospho-Y18 by protein tyrosine phosphatase SHP2 in vitro. Since both tau and SHP2 play a critical role in NGF-induced signaling pathway, these findings raised the possibility that the tau-SHP2 association has a role in NGF signaling.

The aim of this dissertation research is to characterize the tau-SHP2 association and its role in neuronal signaling. Here, we provide evidence that tau phosphorylation is not required for SHP2 association but significantly enhances the interaction. The SHP2 binding region of tau napped to residues 256-273, which contain the microtubule binding repeat 1 of tau. Using in situ proximity ligation assay (PLA), we also showed the presence of endogenous tau-SHP2 and tau-activated SHP2 complexes in neuronal cells. The number of complexes was increased in the cells in response to NGF. Our PLA data also showed the localization of these complexes to actin ruffles. In NGF signaling, we showed that phosphorylation at T231 of tau was necessary for the increase in tau-SHP2 association. Lastly, we provide evidence that tau-SHP2 complexes are present in mouse primary neuronal cultures and mouse brain sections. Together, these findings show a role for tau phosphorylation in SHP2 binding and a potential role for tau-SHP2 interaction in neuronal signal transduction. Based on our findings, we speculate that there is a role for tau-SHP2 association during early brain development and in neurodegenerative disease.

Public Abstract

Alzheimer's disease (AD) is the most prevalent dementia causing cognition-associated problems. Since there is no cure for the disease, development of treatments that will significantly delay or even stop AD is significant.

Our lab has focused on what may be happening during early AD progression at the cellular levels. Survival and behavior of cells are controlled by communications of many proteins inside cells, which are done by dynamic and proper interactions of the proteins. For development of human brain, a specific communication occurring in brain cells is essential. This communication within the cells is also controlled by interactions of numerous proteins. Our lab previously found that a protein, “tau”, could not only participate in but also increase an intracellular communication in neuronal cells. Our lab also found that a protein, “SHP2”, which is also important for the same intracellular communication, interacted with tau. We thus speculated that the interaction between tau and SHP2 may be critical to control the communication involved in brain development. As a result, we found that a specific change in tau protein increased the tau-SHP2 interaction in developing cells, suggesting that such increase in tau-SHP2 interaction may be critical for the increase in the intracellular communication. Since both the same change in tau protein and the brain development-associated communication are also shown in early AD brain, we hope our research to provide valuable information for understanding early AD events, thereby helping find a therapeutic target.

Keywords

Phosphorylation, SHP2, Signal Transduction, Tau

Pages

xiii, 120 pages

Bibliography

Includes bibliographical references (pages 101-120).

Copyright

Copyright © 2017 Yohan Kim

Included in

Cell Biology Commons

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