title: Differential regulation of translation and endocytosis of alternatively spliced forms of the type II bone morphogenetic protein (BMP) receptor.
abstract: The expression and function of transforming growth factor-β superfamily receptors are regulated by multiple molecular mechanisms. The type II BMP receptor (BMPRII) is expressed as two alternatively spliced forms, a long and a short form (BMPRII-LF and -SF, respectively), which differ by an ∼500 amino acid C-terminal extension, unique among TGF-β superfamily receptors. Whereas this extension was proposed to modulate BMPRII signaling output, its contribution to the regulation of receptor expression was not addressed. To map regulatory determinants of BMPRII expression, we compared synthesis, degradation, distribution, and endocytic trafficking of BMPRII isoforms and mutants. We identified translational regulation of BMPRII expression and the contribution of a 3' terminal coding sequence to this process. BMPRII-LF and -SF differed also in their steady-state levels, kinetics of degradation, intracellular distribution, and internalization rates. A single dileucine signal in the C-terminal extension of BMPRII-LF accounted for its faster clathrin-mediated endocytosis relative to BMPRII-SF, accompanied by mildly faster degradation. Higher expression of BMPRII-SF at the plasma membrane resulted in enhanced activation of Smad signaling, stressing the potential importance of the multilayered regulation of BMPRII expression at the plasma membrane.
authors.affiliation: Department of Neurobiology, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Ayelet R
authors.initials: AR
authors.lastname: Amsalem
authors.affiliation: Department of Neurobiology, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Barak
authors.initials: B
authors.lastname: Marom
authors.affiliation: Department of Neurobiology, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Keren E
authors.initials: KE
authors.lastname: Shapira
authors.affiliation: Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Tal
authors.initials: T
authors.lastname: Hirschhorn
authors.affiliation: Department of Neurobiology, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Livia
authors.initials: L
authors.lastname: Preisler
authors.affiliation: Institute for Chemistry and Biochemistry, Freie Univesitaet Berlin, 1495 Berlin, Germany.
authors.forename: Pia
authors.initials: P
authors.lastname: Paarmann
authors.affiliation: Institute for Chemistry and Biochemistry, Freie Univesitaet Berlin, 1495 Berlin, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Knaus
authors.affiliation: Department of Neurobiology, Tel Aviv University, Tel Aviv 69978, Israel henis@post.tau.ac.il marceloe@post.tau.ac.il.
authors.forename: Yoav I
authors.initials: YI
authors.lastname: Henis
authors.affiliation: Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel henis@post.tau.ac.il marceloe@post.tau.ac.il.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Ehrlich
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics / Q000378:metabolism*; D019556:COS Cells; D002462:Cell Membrane / Q000378:metabolism; D002522:Chlorocebus aethiops; D022163:Clathrin-Coated Vesicles / Q000378:metabolism; D004705:Endocytosis; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D009154:Mutation; D014176:Protein Biosynthesis; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051896:Smad Proteins, Receptor-Regulated / Q000378:metabolism
chemical_list: D020033:Protein Isoforms; D018125:Receptors, Transforming Growth Factor beta; D051896:Smad Proteins, Receptor-Regulated; C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II