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

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2013, 2009, 2009, 2014
Li, Hongzhao
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John Wiley & Sons, Inc.
American Society of Hematology
John Wiley & Sons, Inc.
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.
cancer, B cell, migration, chemotaxis, PI3K, PI(3,4)P2, INPP4, TAPP2
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