The Molecular Basis of Leukocyte Adhesion Involving Phosphatidic Acid and Phospholipase D

Defining how leukocytes adhere to solid surfaces, such as capillary beds, and the subsequent migration through the extracellular matrix, is a central biological issue. We show here that phospholipase D (PLD) and its enzymatic reaction product, phosphatidic acid (PA), regulate cell adhesion of immune...

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Bibliographic Details
Published in:The Journal of biological chemistry 2014-10, Vol.289 (42), p.28885-28897
Main Authors: Speranza, Francis, Mahankali, Madhu, Henkels, Karen M., Gomez-Cambronero, Julian
Format: Article
Language:English
Subjects:
Actins - chemistry
Animals
Cell Adhesion
Cell Line
Green Fluorescent Proteins - chemistry
Inflammation
Lipids
Lipids - chemistry
Macrophages - cytology
Macrophages - metabolism
Mice
Neutrophils - cytology
Neutrophils - metabolism
Phosphatidic Acids - chemistry
Phosphatidylcholines - chemistry
Phospholipase D - metabolism
Protein Binding
Signal Transduction
Transfection
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Summary:Defining how leukocytes adhere to solid surfaces, such as capillary beds, and the subsequent migration through the extracellular matrix, is a central biological issue. We show here that phospholipase D (PLD) and its enzymatic reaction product, phosphatidic acid (PA), regulate cell adhesion of immune cells (macrophages and neutrophils) to collagen and have defined the underlying molecular mechanism in a spatio-temporal manner that coincides with PLD activity timing. A rapid (t½ = 4 min) and transient activation of the PLD1 isoform occurs upon adhesion, and a slower (t½ = 7.5 min) but prolonged (>30 min) activation occurs for PLD2. Importantly, PA directly binds to actin-related protein 3 (Arp3) at EC50 = 22 nm, whereas control phosphatidylcholine did not bind. PA-activated Arp3 hastens actin nucleation with a kinetics of t½ = 3 min at 300 nm (compared with controls of no PA, t½ = 5 min). Thus, PLD and PA are intrinsic components of cell adhesion, which reinforce each other in a positive feedback loop and react from cues from their respective solid substrates. In nascent adhesion, PLD1 is key, whereas a sustained adhesion in mature or established focal points is dependent upon PLD2, PA, and Arp3. A prolonged adhesion could effectively counteract the reversible intrinsic nature of this cellular process and constitute a key player in chronic inflammation.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M114.597146