Differential regulation of translation and endocytosis of alternatively spliced forms of the type II bone morphogenetic protein (BMP) receptor

• Published in: Molecular biology of the cell Vol. 27; no. 4; pp. 716 - 730
• Main Authors: Amsalem, Ayelet R, Marom, Barak, Shapira, Keren E, Hirschhorn, Tal, Preisler, Livia, Paarmann, Pia, Knaus, Petra, Henis, Yoav I, Ehrlich, Marcelo
• Format: Journal Article
• Language: English
• Published: United States The American Society for Cell Biology 15.02.2016
• Subjects: Alternative Splicing; Animals; Bone Morphogenetic Protein Receptors, Type II - genetics; Bone Morphogenetic Protein Receptors, Type II - metabolism; Cell Membrane - metabolism; Cercopithecus aethiops; Clathrin-Coated Vesicles - metabolism; COS Cells; Endocytosis; Gene Expression Regulation; HEK293 Cells; Humans; Mutation; Protein Biosynthesis; Protein Isoforms - genetics; Protein Isoforms - metabolism; Proteolysis; Receptors, Transforming Growth Factor beta - genetics; Receptors, Transforming Growth Factor beta - metabolism; Signal Transduction; Smad Proteins, Receptor-Regulated - metabolism
• ISSN: 1059-1524; 1939-4586
• DOI: 10.1091/mbc.e15-08-0547

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.