title: BRAF activates PAX3 to control muscle precursor cell migration during forelimb muscle development.
abstract: Migration of skeletal muscle precursor cells is a key step during limb muscle development and depends on the activity of PAX3 and MET. Here, we demonstrate that BRAF serves a crucial function in formation of limb skeletal muscles during mouse embryogenesis downstream of MET and acts as a potent inducer of myoblast cell migration. We found that a fraction of BRAF accumulates in the nucleus after activation and endosomal transport to a perinuclear position. Mass spectrometry based screening for potential interaction partners revealed that BRAF interacts and phosphorylates PAX3. Mutation of BRAF dependent phosphorylation sites in PAX3 impaired the ability of PAX3 to promote migration of C2C12 myoblasts indicating that BRAF directly activates PAX3. Since PAX3 stimulates transcription of theMetgene we propose that MET signaling via BRAF fuels a positive feedback loop, which maintains high levels of PAX3 and MET activity required for limb muscle precursor cell migration.
authors.affiliation: Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany.
authors.forename: Jaeyoung
authors.initials: J
authors.lastname: Shin
authors.affiliation: Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Watanabe
authors.affiliation: Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany.
authors.forename: Soraya
authors.initials: S
authors.lastname: Hoelper
authors.affiliation: Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Krüger
authors.affiliation: Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany.
authors.forename: Sawa
authors.identifier: 0000-0002-1594-9476
authors.initials: S
authors.lastname: Kostin
authors.affiliation: Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Pöling
authors.affiliation: Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kubin
authors.affiliation: Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany.
authors.forename: Thomas
authors.identifier: 0000-0002-6165-4804
authors.initials: T
authors.lastname: Braun
mesh_terms: D000818:Animals; D002465:Cell Movement; D005552:Forelimb / Q000196:embryology*; D018507:Gene Expression Regulation, Developmental; D013058:Mass Spectrometry; D051379:Mice; D008954:Models, Biological; D024510:Muscle Development; D000072041:PAX3 Transcription Factor / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D025941:Protein Interaction Mapping; D011499:Protein Processing, Post-Translational; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism*; D013234:Stem Cells / Q000502:physiology*
chemical_list: D000072041:PAX3 Transcription Factor; C068686:Pax3 protein, mouse; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf
keywords: B-Raf; Pax3; Skeletal muscle development; cell biology; cell migration; chicken; developmental biology; endosomal trafficking; intracellular signaling; mouse; stem cells