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Mechanism and consequence of P75 Signaling
Harrington, Anthony W

2005, Doctor of Philosophy, Ohio State University, Biochemistry.
The neurotrophin receptor p75 is responsible for a wide variety of signaling essential for proper development of the nervous system including cell survival and cell death. The first identified role of p75 was in augmenting Trk dependent survival and differentiation. However, p75 can also signal independently of Trks to promote apoptosis. The goal of this thesis was to understand the mechanism of p75-mediated cell death and to determine the in vivo consequences of p75 signaling. P75 is known to be induced in neurons and glia following injury. We therefore examined the outcome of this p75 induction in vivo. P75 was found to play a pro-apoptotic role following axotomy injury in the brain and spinal cord. Our analyses of neurotrophin expression after injury revealed that NGF is induced primarily as the precursor form, ProNGF. ProNGF was responsible for activating p75 following injury. In terms of the signaling pathway activated by p75, cJun N-terminal Kinase (JNK) was known to be involved. We found that activation of a small G protein Rac is necessary for JNK activation and apoptosis. P75 can also activate Rho in cooperation with the Nogo Receptor, leading to inhibition of axon growth. We identified a duel RhoGEF, Kalirin 9, as a p75 interacting protein. Kalirin 9 binding to p75 is regulated by NgR, and its activity GDP/GTP exchange activity is required for Rho activation by NgR and p75. A transgenic mouse expressing a dominant negative Kalirin 9 is able to suppress injury-mediated Rho activation suggesting Kalirin 9 is the exchange factor responsible for Rho activation by p75 and NgR after spinal cord injury. These findings demonstrate the important roles for the small G proteins Rac and Rho in p75 signaling.
Sung Ok Yoon (Advisor)
225 p.

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Harrington, A. (2005). Mechanism and consequence of P75 Signaling. (Electronic Thesis or Dissertation). Retrieved from https://etd.ohiolink.edu/

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Harrington, Anthony. "Mechanism and consequence of P75 Signaling." Electronic Thesis or Dissertation. Ohio State University, 2005. OhioLINK Electronic Theses and Dissertations Center. 22 May 2015.

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Harrington, Anthony "Mechanism and consequence of P75 Signaling." Electronic Thesis or Dissertation. Ohio State University, 2005. https://etd.ohiolink.edu/

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