Abstract
Augmented AMP-activated protein kinase (AMPK) activity inhibits cell migration, possibly contributing to the clinical benefits of chemical AMPK activators in preventing atherosclerosis, vascular remodelling and cancer metastasis. However, the underlying mechanisms remain largely unknown. Here we identify PDZ and LIM domain 5 (Pdlim5) as a novel AMPK substrate and show that it plays a critical role in the inhibition of cell migration. AMPK directly phosphorylates Pdlim5 at Ser177. Exogenous expression of phosphomimetic S177D-Pdlim5 inhibits cell migration and attenuates lamellipodia formation. Consistent with this observation, S177D-Pdlim5 suppresses Rac1 activity at the cell periphery and displaces the Arp2/3 complex from the leading edge. Notably, S177D-Pdlim5, but not WT-Pdlim5, attenuates the association with Rac1-specific guanine nucleotide exchange factors at the cell periphery. Taken together, our findings indicate that phosphorylation of Pdlim5 on Ser177 by AMPK mediates inhibition of cell migration by suppressing the Rac1-Arp2/3 signalling pathway.
Highlights
Augmented AMP-activated protein kinase (AMPK) activity inhibits cell migration, possibly contributing to the clinical benefits of chemical AMPK activators in preventing atherosclerosis, vascular remodelling and cancer metastasis
We previously reported that AMPK regulates cell migration by controlling microtubule dynamics through phosphorylation of a cytoplasmic linker protein-170 (CLIP-170)[4]
We identified PDZ and LIM domain 5 (Pdlim5)[18] as a novel substrate of AMPK; Pdlim[5] is directly phosphorylated by AMPK at Ser[177]
Summary
Augmented AMP-activated protein kinase (AMPK) activity inhibits cell migration, possibly contributing to the clinical benefits of chemical AMPK activators in preventing atherosclerosis, vascular remodelling and cancer metastasis. Exogenous expression of phosphomimetic S177D-Pdlim[5] inhibits cell migration and attenuates lamellipodia formation Consistent with this observation, S177D-Pdlim[5] suppresses Rac[1] activity at the cell periphery and displaces the Arp2/3 complex from the leading edge. We identified PDZ and LIM domain 5 (Pdlim5)[18] as a novel substrate of AMPK; Pdlim[5] is directly phosphorylated by AMPK at Ser[177] This phosphorylation results in displacement of Rho GEF 6 (Arhgef6), a Rac1/Cdc42-specific GEF and known as p21-activated kinase-interacting exchange factor-aPIX, from the leading edge of the cell by disrupting the association between Pdlim[5] and Arhgef[6]. We propose that Pdlim[5] is the main signalling molecule that regulates cell migration in the context of augmented AMPK activity
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