Role of SMURF1 ubiquitin ligase in BMP receptor trafficking and signaling.
Heterozygous germline mutations in the bone morphogenetic protein type II receptor gene (BMPRII) are associated with hereditary pulmonary arterial hypertension (HPAH). Missense mutations, both in the extracellular ligand-binding and cytoplasmic kinase domains, mostly involve substitution of conserved Cys residues. Singular substitution at any of those Cys residues causes cytoplasmic, perinuclear localization of BMPR with reduced cell surface expression and BMP signaling. The present study examined the effect of Cys residue substitution on BMPR endocytic trafficking and lysosome degradation. We demonstrate that endocytosis/lysosomal degradation of BMPR occurs by two distinct pathways. SMURF1 ubiquitin ligase induces lysosomal degradation of BMPR, while ligase-inactive SMURF1 maintains BMPR protein level and cell surface expression. Substitution of BMPR Cys residues increases lysosomal degradation which is blocked by ligase-inactive SMURF1, elevating protein levels of Cys-substituted BMPRs. Expression of Cys-substituted BMPR suppresses basal BMP signaling activity which is also up-regulated by ligase-inactive SMURF1. Cys-residue substitution thus appears to cause BMPR endocytosis to lysosomes in a SMURF1 ubiquitin ligase-associated pathway. Kinase-activated BMPR undergoes endocytic/lysosomal degradation by a pathway with certain unique properties. Therefore, our results describe a novel mechanism whereby SMURF1 ubiquitin ligase regulates constitutive endocytosis of BMPR which may be mediated by its conserved Cys residues.
['Murakami|Koko|K|', 'Etlinger|Joseph D|JD|']
D000818:Animals D052006:Bone Morphogenetic Protein Receptors, Type II D019556:COS Cells D002522:Chlorocebus aethiops D004705:Endocytosis D057809:HEK293 Cells D006801:Humans D008247:Lysosomes D021381:Protein Transport D059748:Proteolysis D015398:Signal Transduction D044767:Ubiquitin-Protein Ligases
SMURF1 ubiquitin ligase Hereditary pulmonary arterial hypertension Conserved cysteine residues of BMP receptor Membrane receptor endocytosis Ser/Thr protein kinase