IDEALS Home University of Illinois at Urbana-Champaign logo The Alma Mater The Main Quad

Molecular mechanisms of signal transduction in neutrophil chemotaxis

Show full item record

Bookmark or cite this item: http://hdl.handle.net/2142/24433

Files in this item

File Description Format
PDF He_Yuan.pdf (4MB) (no description provided) PDF
Title: Molecular mechanisms of signal transduction in neutrophil chemotaxis
Author(s): He, Yuan
Director of Research: Wang, Fei
Doctoral Committee Chair(s): Chen, Jie
Doctoral Committee Member(s): Wang, Fei; Newmark, Phillip A.; Brieher, William M.; Xiang, Yang
Department / Program: Cell & Developmental Biology
Discipline: Cell and Developmental Biology
Degree Granting Institution: University of Illinois at Urbana-Champaign
Degree: Ph.D.
Genre: Dissertation
Subject(s): cell migration neutrophil chemotaxis cell signaling Lyn Ras-proximate-1 (Rap1) integrin Rapamycin complex 2 (mTORC2) Rac actin
Abstract: Neutrophils play a critical role in host defense against invading pathogens. Chemotaxis, the directed migration of cells, allows neutrophil to seek out the sites of inflammation and infection. Neutrophil chemotaxis as well as other type of cell migration are considered as cycles composed of highly orchestrated steps. Recently the underlying signaling mechanisms of neutrophil chemotaxis are better understood with the studies in knockout mice and neutrophil-like cell lines: a number of signaling molecules in neutrophil chemotaxis have been identified, and a feedback loop-based model of “frontness” and “backness” pathways has been proposed to explain the establishment of neutrophil polarity and chemotaxis. However, the signaling mechanisms that control actin cytoskeleton reorganization and interaction between the cells and the substratum on which cells migrate are still not fully understood. In my first research project, we have identified a signaling pathway, mediated by non-receptor tyrosine kinase Lyn that is essential for localized integrin activation, leading edge attachment, and persistent migration during neutrophil chemotaxis. This pathway depends upon Gi protein-mediated activation and leading edge recruitment of Lyn. We documented the small GTPase Rap1 as a major downstream effector of Lyn to regulate neutrophil adhesion during chemotaxis. Depletion of Lyn abolished chemoattractant-induced Rap1 activation at the cell's leading edge. Furthermore, Lyn controls spatial activation of Rap1 by recruiting the CrkL/C3G protein complex to the leading edge. Together, these results provide novel mechanistic insights into the poorly understood signaling network that controls leading edge adhesion during neutrophil chemotaxis. In my second research project, we have explored the role of mammalian Target of Rapamycin complex 2 (mTORC2) in neutrophil chemotaxis. Lines of evidence indicate that mTORC2 is essential for the dynamics of actin cytoskeleton: depletion of mTORC2 impairs the organization of actin cytoskeleton in mammalian cells, and knockout of mTORC2 inhibit chemotaxis in D. discoideum through PKB mediated signaling pathway. In our studies, we found that mTORC2 is essential for neutrophil chemotaxis. Depletion of mTORC2, not mTORC1, abolishes fMLP-induced actin polymerization and chemotaxis in dHL-60 cells. Pharmacological inhibition of mTOR kinase activity and AKT phosphorylation fails to affect actin polymerization and chemotaxis in both human neutrophils and dHL-60 cells. We further demonstrated that mTORC2 is required for fMLP-induced Rac activation. After chemoattractant stimulation, mTORC2 translocates to and accumulates at the leading edge of chemotactic cells. Taken together, our findings indicate that mTORC2 is essential for neutrophil chemotaxis by controlling actin polymerization-mediated leading edge protrusion during neutrophil chemotaxis.
Issue Date: 2011-05-25
URI: http://hdl.handle.net/2142/24433
Rights Information: Copyright 2011 Yuan He
Date Available in IDEALS: 2011-05-25
2013-05-26
Date Deposited: 2011-05
 

This item appears in the following Collection(s)

Show full item record

Item Statistics

  • Total Downloads: 145
  • Downloads this Month: 3
  • Downloads Today: 0

Browse

My Account

Information

Access Key