Serum-induced phosphorylation of the serum response factor coactivator MKL1 by the extracellular signal-regulated kinase 1/2 pathway inhibits its nuclear localization.

Abstract

Megakaryoblastic leukemia 1 (MKL1) is a myocardin-related coactivator of the serum response factor (SRF) transcription factor, which has an integral role in differentiation, migration, and proliferation. Serum induces RhoA-dependent translocation of MKL1 from the cytoplasm to the nucleus and also causes a rapid increase in MKL1 phosphorylation. We have mapped a serum-inducible phosphorylation site and found, surprisingly, that its mutation causes constitutive localization to the nucleus, suggesting that phosphorylation of MKL1 inhibits its serum-induced nuclear localization. The key site, serine 454, resembles a mitogen-activated protein kinase phosphorylation site, and its modification was blocked by the MEK1 inhibitor U0126, implying that extracellular signal-regulated kinase 1/2 (ERK1/2) is the serum-inducible kinase that phosphorylates MKL1. Previous results indicated that G-actin binding to MKL1 promotes its nuclear export, and we found that MKL1 phosphorylation is required for its binding to actin, explaining its effect on localization. We propose a model in which serum induction initially stimulates MKL1 nuclear localization due to a decrease in G-actin levels, but MKL1 is then downregulated by nuclear export due to ERK1/2 phosphorylation.

• Authors: Susanne Muehlich, Ruigong Wang, Seung-Min Lee, Thera C Lewis, Chao Dai, Ron Prywes
• Journal: Molecular and cellular biology (Mol Cell Biol) Vol. 28 Issue 20 Pg. 6302-13 (Oct 2008) ISSN: 1098-5549 [Electronic] United States
• PMID: 18694962 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Actins
• DNA-Binding Proteins
• MRTFA protein, human
• Oncogene Proteins, Fusion
• Serum Response Factor
• Trans-Activators
• Phosphoserine
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• Tetradecanoylphorbol Acetate

Topics

• Actins (metabolism)
• Amino Acid Sequence
• Animals
• Cell Nucleus (drug effects, enzymology)
• DNA-Binding Proteins (chemistry, metabolism)
• HeLa Cells
• Humans
• Mice
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• Molecular Sequence Data
• Mutation (genetics)
• Oncogene Proteins, Fusion (chemistry, metabolism)
• Phosphorylation (drug effects)
• Phosphoserine (metabolism)
• Protein Binding (drug effects)
• Protein Transport (drug effects)
• Serum
• Serum Response Factor (metabolism)
• Tetradecanoylphorbol Acetate (pharmacology)
• Trans-Activators