Serum-induced phosphorylation of the serum response factor coactivator MKL1 by the extracellular signal-regulated kinase 1/2 pathway inhibits its nuclear localization.
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.
Muehlich
Susanne
S
Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
Wang
Ruigong
R
Lee
Seung-Min
SM
Lewis
Thera C
TC
Dai
Chao
C
Prywes
Ron
R
D000199:Actins / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D002467:Cell Nucleus / Q000187:drug effects / Q000201:enzymology*; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D044967:Serum; D026362:Serum Response Factor / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D015534:Trans-Activators
D000199:Actins; D004268:DNA-Binding Proteins; C431575:MRTFA protein, human; D015514:Oncogene Proteins, Fusion; D026362:Serum Response Factor; D015534:Trans-Activators; D010768:Phosphoserine; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D013755:Tetradecanoylphorbol Acetate