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Pyk2‐Induced Tyrosine Phosphorylation of STIM1 at Y361 Residue Regulates Puncta Formation, Store‐Operated Calcium Entry and Lung Vascular Permeability
Author(s) -
Tauseef Mohammad,
Sharma Tiffany,
Malik Asrar,
Mehta Dolly
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.661.9
Subject(s) - stim1 , microbiology and biotechnology , tyrosine phosphorylation , phosphorylation , endoplasmic reticulum , chemistry , tyrosine , tyrosine kinase , biology , signal transduction , biochemistry
Store‐operated Ca 2+ entry (SOCE) through transient receptor potential canonical channels (TRPCs) regulate the increase in intracellular calcium (Ca 2+ ) in endothelial cells. Upon endoplasmic reticulum (ER) Ca 2+ store depletion, STIM1 has been shown to form puncta and translocation near plasma membrane to induce SOCE. Yet, mechanisms regulating STIM1 oligomerization and translocation to the plasma membrane fundamental to activation to SOCE remain unclear. We show that thrombin as well as thapsigargin (a direct activator of SOCE) rapidly induced the tyrosine phosphorylation of STIM1 in lung endothelial cells in association with STIM1 puncta formation. STIM1 protein contains six tyrosine residues (Y98, Y130, Y150, Y231, Y316, Y361). Mutating all tyrosine residues in STIM1 protein to phenylalanine (Y‐F) suppressed SOCE. Intriguingly, mutation of Y361àF in STIM1 that lies within oligomerization domain also abrogated SOCE. We identify proline‐rich tyrosine kinase (Pyk2) as the kinase inducing STIM1 phosphorylation. We also show that overexpression of Y361‐phosphodefective mutant in WT mice endothelial cells (ECs) using liposomes conjugated with endothelial‐specific VE‐cadherin promoter cDNA prevented LPS induced pulmonary vascular permeability. Thus, our studies suggest that STIM1 phosphorylation at tyrosine (Y) 361 residue induces puncta formation and thereby play a key role in regulating SOCE and increase in endothelial permeability.