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Stathmin modulates microtubule dynamics and controls Rho signaling and vascular permeability
Author(s) -
Birukova Anna A,
Sarich Nicolene,
Wu Tinghuai,
Tian Xinyong
Publication year - 2013
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.27.1_supplement.1131.3
Subject(s) - stathmin , microbiology and biotechnology , cytoskeleton , microtubule , phosphorylation , dephosphorylation , thrombin , crosstalk , rhoa , chemistry , signal transduction , biology , biochemistry , cell , immunology , platelet , physics , optics , phosphatase
Crosstalk between microtubules (MT) and actin cytoskeleton is involved in Rho GTPase‐dependent regulation on endothelial (EC) permeability, however precise mechanisms of Rho regulation by MT remain poorly understood. We studied a role of stathmin, the MT‐associated protein controlling MT stability, in the mediation of agonist‐induced permeability and vascular leak. Thrombin treatment of human pulmonary EC induced rapid dephosphorylation of stathmin leading to MT disassembly and activation of feedback signaling by another MT‐bound protein, tau, which further promoted MT disassembly. Inhibition of stathmin activity abrogated thrombin‐induced cytoskeletal remodeling and Rho‐dependent EC hyperpermeability, while expression of a phosphorylation deficient stathmin mutant exacerbated thrombin‐induced EC barrier disruption. Stathmin inhibition preserved the MT network and prevented thrombin‐induced tau‐dependent MT disassembly, and suppressed release of Rho‐specific guanine nucleotide exchange factor, GEF‐H1. Protective effects of stathmin knockdown were observed in vivo in the two‐hit model of ventilator induced lung injury. These results demonstrate the mechanism of stathmin‐dependent control of MT dynamics and suggest novel potential pharmacological interventions in the prevention of increased vascular leak via modulation of stathmin activity. Funding: NHLBI HL089257, HL107920