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Methods to Study Mrp4-containing Macromolecular Complexes in the Regulation of Fibroblast Migration
Published on: May 19, 2016
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Augmented AMPK activity inhibits cell migration by phosphorylating the novel substrate Pdlim5
Yi Yan1, Osamu Tsukamoto1, Atsushi Nakano2
1Department of Medical Biochemistry, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Nature Communications
|January 31, 2015
Summary
AMP-activated protein kinase (AMPK) inhibits cell migration by phosphorylating PDZ and LIM domain 5 (Pdlim5). This phosphorylation suppresses Rac1-Arp2/3 signaling, offering insights into AMPK activator benefits for diseases like atherosclerosis and cancer.
Area of Science:
- Molecular Biology
- Cell Biology
- Biochemistry
Background:
- AMP-activated protein kinase (AMPK) activation inhibits cell migration.
- AMPK activators show clinical benefits in atherosclerosis, vascular remodeling, and cancer metastasis.
- Mechanisms underlying AMPK's role in cell migration inhibition are largely unknown.
Purpose of the Study:
- Identify novel AMPK substrates involved in cell migration.
- Elucidate the role of PDZ and LIM domain 5 (Pdlim5) in AMPK-mediated cell migration inhibition.
Main Methods:
- Investigated Pdlim5 as a direct AMPK substrate.
- Utilized phosphomimetic mutations (S177D-Pdlim5) to study phosphorylation effects.
- Assessed effects on cell migration, lamellipodia formation, and Rac1/Arp2/3 complex activity.
Main Results:
- Identified Pdlim5 as a novel AMPK substrate, phosphorylated at Ser177.
- Phosphomimetic S177D-Pdlim5 expression inhibited cell migration and lamellipodia formation.
- S177D-Pdlim5 suppressed peripheral Rac1 activity and displaced the Arp2/3 complex.
- S177D-Pdlim5 attenuated interactions with Rac1 guanine nucleotide exchange factors.
Conclusions:
- AMPK phosphorylation of Pdlim5 at Ser177 is a key mechanism for inhibiting cell migration.
- This pathway involves the suppression of the Rac1-Arp2/3 signaling cascade.
- Findings provide molecular insights into the therapeutic potential of AMPK activators.
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