Periostin/β1integrin interaction regulates p21-activated kinases in valvular interstitial cell survival and in actin cytoskeleton reorganization.


Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA.. Electronic address: [Email]


The matricellular protein periostin (PN) promotes postnatal valve remodeling and maturation. Incomplete remodeling of the valve can trigger degenerative processes that lead to a myxomatous phenotype that includes loss of PN. However, signaling pathways involved that link valvular-interstitial-fibroblast cells (VICs) to proliferation, migration and actin remodeling functions are unclear. The p21-activated kinases (Paks) have been shown to regulate cytoskeleton rearrangements and cell proliferation/adhesion/migration functions in a variety of cellular contexts, including normal cells and cancer cells. This study shows that Pak1, but not Pak2 and Pak4, is a critical mediator of VIC survival and actin organization, and that the molecular signaling regulating actin-remodeling is initiated upon PN/beta-integrin-induced phosphorylation of the focal-adhesion-kinase (Fak) (Y397). Molecular and pharmacological inhibition of key components of PN/Fak/Akt1 signaling abolished the PN-induced actin polymerization and the activation of mTOR, p70S6K and Pak1. Similarly, blocking mTOR inhibited p70S6K, Pak1 phosphorylation and consequently actin-polymerization. Accordingly, inhibiting p70S6K blocked Pak1 phosphorylation and actin polymerization, and subsequently inhibited adhesion and growth of VICs. Periostin-induced Akt1 activation of Pak1 is independent of Cdc42 and Rac1 GTPases, and Akt1 is both downstream and upstream of Pak1. Further, the PN-Pak1-induced Akt1 protects cells from apoptosis through suppression of transcriptional activation of Forkhead-Transcription-Factor (FKHR). In contrast, kinase deficient Pak1 increases apoptosis by increasing FKHR-mediated transcriptional activation. These studies define new functional significance of PN-Fak-Akt1-Pak1 signaling that at least partly regulates Akt1-induced actin polymerization and FKHR-mediated transcriptional activation, which may eventually regulate the mature-valve-leaflet remodeling function, and also FKHR-mediated transcriptional activation for pro-survival of VICs.


Actin-remodeling,Fak,Pak1,Periostin,Valve-interstitial-fibroblast cell,α5β1-integrin,

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