Dual regulation of cofilin activity by LIM kinase and slingshot-1L phosphatase controls platelet-derived growth factor-induced migration of human aortic smooth muscle cells

Alejandra San Martín, Moo Yeol Lee, Holly C. Williams, Kensaku Mizuno, Bernard Lassègue, Kathy K. Griendling

Research output: Contribution to journalArticlepeer-review

50 Citations (Scopus)

Abstract

Platelet-derived growth factor (PDGF) plays a central role in vascular healing, atherosclerosis, and restenosis, partly by stimulating vascular smooth muscle cell (VSMC) migration. Migration requires rapid turnover of actin filaments, which is partially controlled by cofilin. Although cofilin is negatively regulated by Ser3 phosphorylation, the upstream signaling pathways have not been defined, nor has its role in VSMC migration been studied. We hypothesized that PDGF-induced migration of VSMCs involves cofilin activation and that this is regulated by the serine kinase LIM kinase (LIMK) and the novel phosphatase Slingshot (SSH)1L. In human VSMCs, stimulation with PDGF increased G-actin incorporation into the actin cytoskeleton. PDGF transiently activated the cofilin kinase, LIMK, with a peak at 5 minutes. However, cofilin was dephosphorylated between 5 and 45 minutes, with a maximum of 43±5% dephosphorylation at 30 minutes, suggesting that PDGF also activates a cofilin phosphatase. We found that VSMCs express SSH1L, which is induced and activated (564±73 versus 1021±141 picomoles of PO4; P=0.015) by PDGF. Of importance, small interfering RNA directed against SSH1L blocked cofilin dephosphorylation and decreased migration (528±33 versus 318±25 cells/field; P<0.01). Taken together, our results suggest that PDGF participates in actin dynamics by dual regulation of cofilin activity via LIMK and SSH1L.

Original languageEnglish
Pages (from-to)432-438
Number of pages7
JournalCirculation research
Volume102
Issue number4
DOIs
Publication statusPublished - 2008 Feb

Keywords

  • LIMK
  • Migration
  • Platelet-derived growth factor
  • Slingshot phosphatase
  • Vascular smooth muscle

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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