Negative regulation of the EGFR-MAPK cascade by actin-MAL-mediated Mig6/Errfi-1 induction.
We analyzed the G-actin-regulated transcriptome by gene expression analysis using previously characterized actin-binding drugs. We found many known MAL/MRTF-dependent target genes of serum response factor (SRF), as well as additional directly regulated genes. Surprisingly, several putative antiproliferative target genes were identified, including mig6/errfi-1, a negative regulator of the EGFR family. Mig6 induction occurred through actin-MAL-SRF signaling, and MAL was inducibly recruited to and activated a mig6 promoter element. Upregulation of Mig6 by lipid agonists such as LPA and S1P or actin drugs involved MAL and correlated with decreased activation of EGFR, MAPK/Erk, and c-fos. Mig6 depletion restored EGFR signaling and provided a proliferative advantage. Overexpression of MAL exhibited strong antiproliferative effects requiring the domains for SRF binding and transactivation, which supports antagonistic functions of MAL on growth-promoting signals. Our results show the existence of negatively acting transcriptional networks between pro- and antiproliferative signaling pathways toward SRF.
Descot
Arnaud
A
Department of Molecular Biology, Max-Planck-Institute of Biochemistry, Martinsried, Germany.
Hoffmann
Reinhard
R
Shaposhnikov
Dmitry
D
Reschke
Markus
M
Ullrich
Axel
A
Posern
Guido
G
D000199:Actins / Q000502:physiology*; D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002460:Cell Line; D049109:Cell Proliferation; D003513:Cycloheximide / Q000494:pharmacology; D015638:Cytochalasin D / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D020935:MAP Kinase Signaling System / Q000187:drug effects; D026901:Membrane Transport Proteins / Q000502:physiology*; D051379:Mice; D009185:Myelin Proteins / Q000502:physiology*; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D011510:Proteolipids / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D053778:Thiazolidines / Q000494:pharmacology; D025521:Tumor Suppressor Proteins
D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D019086:Bridged Bicyclo Compounds, Heterocyclic; C484017:ERRFI1 protein, human; C475819:Errfi1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; C569026:MAL protein, human; C569027:Mal protein, mouse; D026901:Membrane Transport Proteins; D009185:Myelin Proteins; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins; D019384:Nucleic Acid Synthesis Inhibitors; D011510:Proteolipids; D012333:RNA, Messenger; D053778:Thiazolidines; D025521:Tumor Suppressor Proteins; D015638:Cytochalasin D; D003513:Cycloheximide; D066246:ErbB Receptors; C037068:latrunculin B