Memory and Decoding in Signaling Transduction Pathways

Author: Kim, Kibeom

Year: 2019

Degree: Dissertation (Ph.D.)

Advisor: Goentoro, Lea A.

Committee Members: Elowitz, Michael B.; Hay, Bruce A.; Goentoro, Lea A.; Zinn, Kai George

Option: Systems Biology

DOI: 10.7907/BJDQ-JX45

Abstract

Intercellular communication allows cells to broadcast and receive necessary information for decision making, and is essential for development, growth, and maintenance of a community of cells in a multicellular organism. Signaling pathways are highly conserved systems of communication between cells, each composed of a distinct network of protein interactions that detect extracellular signal and transduce the signal information for cellular response. A signaling pathway typically encodes information from signaling events into dynamics of second messengers, intracellular molecules in the signaling pathway that activate in response to signal and initiate cellular response. Therefore, understanding how information is encoded in second messenger dynamics, and how transcriptional machinery decode and generate output response is an important aspect in investigating how signaling information is transduced inside a cell. In the first chapter, we investigate the timescales of memory in endogenous β-catenin and Smad3, second messengers in the Wnt and Tgf-β pathways, through single cell timelapse microscopy. The findings demonstrate that both second messengers have short memory and high cell-to-cell variability, and that their memory is tunable through modulating cellular contexts. In the second chapter, we investigate decoding of information from β-catenin in the Wnt pathway. We identify a novel 11-bp DNA element that recruit β-catenin for transcriptional suppression. This negative regulatory element is shown to act in conjunction with the canonical Wnt responsive element to form an incoherent feedforward loop (IFFL). Through mathematical simulations, we present how the IFFL circuit can generate complex output functions in decoding β-catenin dynamics, which include those that confer robustness against perturbations in signaling response such as band-pass filtering and fold change detection.

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