BETA-ARRESTIN MEDIATED CELL CHEMOTAXIS

Arrestin;Chemotaxis;Scaffold;Model;Simulation;Adaptation;Signaling;Pathway;Microfluidics;Biomedical Engineering

Chang, HaoIglesias, Pablo A. ;

Johns Hopkins University

关键词: Arrestin;    Chemotaxis;    Scaffold;    Model;    Simulation;    Adaptation;    Signaling;    Pathway;    Microfluidics;    Biomedical Engineering;   

Others  :  https://jscholarship.library.jhu.edu/bitstream/handle/1774.2/39321/CHANG-DISSERTATION-2014.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: JOHNS HOPKINS DSpace Repository

【 摘 要 】

Eukaryotic chemotactic signaling networks which regulate the cell’s ability to sense the gradient of chemotactic cues frequently have the dual property of perfect adaptation to spatially homogeneous inputs, and persistent activation by inputs that are spatially graded. This property is also shared by bacterial chemotaxis networks, raising the question of whether these two types of chemotactic processes also have similar organizations of the underlying biomolecular processes. Interestingly, perfect adaptation can only be achieved robustly through a handful of mechanisms. Eukaryotic chemotactic networks appear to rely on one of these—the incoherent feed-forward loop, while bacterial chemotaxis depends on another—the negative feedback loop. In this dissertation, we will discuss how this conclusion can be reached even if the details of the molecular networks are incompletely understood. Furthermore, we argue that the use of distinct network architectures is not accidental and may be a consequence of the nature of the signaling inputs and the limitations of the sensory properties of different cell types.Biological systems always appear as diverse and complicated. Not all the chemotaxis can be classified into the two categories we discussed above. For example, the beta-arrestin2, an important G-protein coupled receptor signaling mediator and scaffold, -mediated cell chemotaxis did not show perfect adaptation. We explored the mechanisms by both experimental and computational approaches and found that the beta-arrestin2 is the key component in the chemotaxis pathways in several aspects: 1) It prompts receptor desensitization to achieve non-perfect adaptation; 2) It assembles signaling complex to response to the input gradients; 3) It amplifies the external gradient by its unique scaffold biphasic regulation; 4) It organizes the receptor recycling to achieve persistent gradient sensing capacity; 5) It reorganizes the cytoskeleton during cell chemotaxis. Due to the biphasic regulation, the scaffold level is important in signal transduction. By manipulating the expression and distribution of the beta-arrestin2, we can convert chemoattractance to chemorepulsion or co-existence of both.