Smad　ubiquitination　regulatory　factor　1　(Smurf1),　an　homologous　to　E6AP　C-terminus　(HECT)-type　E3　ubiquitin　ligase,　performs　a　crucial　role　in　the　regulation　of　the　bone　morphogenetic　protein　(BMP)　signalling　pathway　in　both　embryonic　development　and　bone　remodelling.　How　the　stability　and　activity　of　Smurf1　are　negatively　regulated　remains　largely　unclear.　Here,　we　report　that　F-box　and　LRR　domain-containing　protein　15　(FBXL15),　an　F-box　protein　of　the　FBXL　family,　forms　an　Skp1-Cullin1-F-box　protein-Roc1　(SCF)(FBXL15)　ubiquitin　ligase　complex　and　targets　Smurf1　for　ubiquitination　and　proteasomal　degradation.　FBXL15,　through　its　leucine-rich　repeat　domain,　specifically　recognizes　the　large　subdomain　within　the　N-lobe　of　the　Smurf1　HECT　domain　and　promotes　the　ubiquitination　of　Smurf1　on　K355　and　K357　within　the　WW-HECT　linker　region.　In　this　way,　FBXL15　positively　regulates　BMP　signalling　in　mammalian　cells.　Knockdown　of　fbxl15　expression　in　zebrafish　embryos　by　specific　antisense　morpholinos　causes　embryonic　dorsalization　phenocoping　BMP-deficient　mutants.　Injection　of　FBXL15　siRNAs　into　rat　bone　tissues　leads　to　a　significant　loss　of　bone　mass　and　decrease　in　bone　mineral　density.　Collectively,　our　results　demonstrate　that　Smurf1　stability　is　suppressed　by　SCFFBXL15　-mediated　ubiquitination　and　that　FBXL15　is　a　key　regulator　of　BMP　signalling　during　embryonic　development　and　adult　bone　formation.　The　EMBO　Journal　(2011)　30,　2675-2689.　doi:10.1038/emboj.2011.155;　Published　online　13　May　2011