• Refine Query
  • Source
  • Publication year
  • to
  • Language
  • No language data
  • Tagged with
  • 1
  • 1
  • 1
  • 1
  • 1
  • 1
  • 1
  • 1
  • 1
  • 1
  • 1
  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

Regulation of malignant B cell migration by PI(3,4)P2-specific phosphatases and binding proteins

Li, Hongzhao January 2014 (has links)
Cell migration is critical to a wide range of physiological and pathological events and is central to disease progression of B lymphocyte (B cell)-derived leukemia and lymphoma as well as many other types of cancer. It is extensively controlled by phosphoinositide 3-kinase (PI3K), which generates PI(3,4,5)P3 (PIP3) and PI(3,4)P2, lipid messengers that recruit pleckstrin homology (PH)-domain-containing signaling proteins. While PIP3 is known to regulate cell migration, it remains a major unanswered question in the field whether PI(3,4)P2 is also implicated in this cellular function. A series of investigations here on PI(3,4)P2-specific lipid phosphatases and binding proteins in the context of chemotaxing malignant B cells provide the first insights into a previously unappreciated role of PI(3,4)P2 signaling in cell migration. First, I used physiological regulators of PI(3,4)P2, the inositol polyphosphate 4-phosphatase (INPP4) enzymes, as tool to manipulate PI(3,4)P2 levels to determine the function of this lipid second messenger. PI(3,4)P2 depletion by INPP4A or INPP4B relative to phosphatase-dead mutants indicated an essential role of PI(3,4)P2 in mediating both the speed and directionality of chemotaxis. Gene silencing of the authenticated PI(3,4)P2-specific binding protein TAPP2 leads to reduced migration speed and directionality, similar to PI(3,4)P2 depletion. The impaired migration is underlain by alterations in chemokine-induced rearrangement of the actin cytoskeleton, loss of migratory polarity and dysregulation of the leading edge activator Rac. A putative PI(3,4)P2-binding protein, lamellipodin (Lpd), is found to strongly colocalize with PI(3,4)P2 depending on the Lpd PH domain. Lpd knock-down rescue experiments indicated that PI(3,4)P2 controls directionality through Lpd, while Lpd also promotes motility independently of PH domain binding to PI(3,4)P2. The PI(3,4)P2-binding protein kinase Akt/PKB (also binds to PIP3) is found to play a positive role in the B cell context. Here, PI(3,4)P2 depletion does not inhibit phosphorylation of Akt but seemingly reduces its activity. It is likely that PI(3,4)P2 mediates malignant B cell migration in part through promoting Akt activity. Taken together, the thesis work establishes the PI(3,4)P2 pathway as a novel branch of the PI3K signaling network controlling cell migration and suggests that PI(3,4)P2 may integrate diverse downstream migratory pathways to impact on cell migration.

Page generated in 0.022 seconds