Fyn kinase mediates cortical actin ring depolymerization required for mast cell migration in response to TGF‐β in mice

Transforming growth factor‐β (TGF‐β) is a potent mast cell (MC) chemoattractant able to modulate local inflammatory reactions. The molecular mechanism leading to TGF‐β‐directed MC migration is not fully described. Here we analyzed the role of the Src family protein kinase Fyn on the main TGF‐β‐induc...

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Bibliographic Details
Published in:European journal of immunology 2017-08, Vol.47 (8), p.1305-1316
Main Authors: Ramírez‐Valadez, Karla A., Vázquez‐Victorio, Genaro, Macías‐Silva, Marina, González‐Espinosa, Claudia
Format: Article
Language:English
Subjects:
actin chemotaxis
Actin Depolymerizing Factors - metabolism
Actins - metabolism
Animals
Chemotaxis
depolymerization
fibrosis
Fyn
mast cells
Mast Cells - immunology
Mast Cells - physiology
Mice
Okadaic Acid - pharmacology
Phosphorylation
PP2A
Protein Phosphatase 2 - metabolism
Proto-Oncogene Proteins c-fyn - genetics
Proto-Oncogene Proteins c-fyn - metabolism
Signal Transduction
Smad2 Protein - metabolism
TGF‐β
Transforming Growth Factor beta - physiology
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Summary:Transforming growth factor‐β (TGF‐β) is a potent mast cell (MC) chemoattractant able to modulate local inflammatory reactions. The molecular mechanism leading to TGF‐β‐directed MC migration is not fully described. Here we analyzed the role of the Src family protein kinase Fyn on the main TGF‐β‐induced cytoskeletal changes leading to MC migration. Utilizing bone marrow‐derived mast cells (BMMCs) from WT and Fyn‐deficient mice we found that BMMC migration to TGF‐β was impaired in the absence of the kinase. TGF‐β caused depolymerization of the cortical actin ring and changes on the phosphorylation of cofilin, LIMK and CAMKII only in WT cells. Defective cofilin activation and phosphorylation of regulatory proteins was detected in Fyn‐deficient BMMCs and this finding correlated with a lower activity of the catalytic subunit of the phosphatase PP2A. Diminished TGF‐β‐induced chemotaxis of Fyn‐deficient cells was also observed in an in vivo model of MC migration (bleomycin‐induced scleroderma). Our results show that Fyn kinase is an important positive effector of TGF‐β‐induced chemotaxis through the control of PP2A activity and this is relevant to pathological processes that are related to TGF‐β‐dependent mast cell migration. Fyn kinase plays a key role on mast cell migration towards TGF‐β by controlling the activation of PP2A phosphatase and cytoskeletal re‐arrangements needed for chemotaxis in vitro and in mouse skin.
ISSN:0014-2980
1521-4141
DOI:10.1002/eji.201646876