Different routes of bone morphogenic protein (BMP) receptor endocytosis influence BMP signaling.
Endocytosis is important for a variety of functions in eukaryotic cells, including the regulation of signaling cascades via transmembrane receptors. The internalization of bone morphogenetic protein (BMP) receptor type I (BRI) and type II (BRII) and its relation to signaling were largely unexplored. Here, we demonstrate that both receptor types undergo constitutive endocytosis via clathrin-coated pits (CCPs) but that only BRII undergoes also caveola-like internalization. Using several complementary approaches, we could show that (i) BMP-2-mediated Smad1/5 phosphorylation occurs at the plasma membrane in nonraft regions, (ii) continuation of Smad signaling resulting in a transcriptional response requires endocytosis via the clathrin-mediated route, and (iii) BMP signaling leading to alkaline phosphatase induction initiates from receptors that fractionate into cholesterol-enriched, detergent-resistant membranes. Furthermore, we show that BRII interacts with Eps15R, a constitutive component of CCPs, and with caveolin-1, the marker protein of caveolae. Taken together, the localization of BMP receptors in distinct membrane domains is prerequisite to their taking different endocytosis routes with specific impacts on Smad-dependent and Smad-independent signaling cascades.
Hartung
Anke
A
Department of Physiological Chemistry II, University of Wuerzburg, Wuerzburg, Germany.
Bitton-Worms
Keren
K
Rechtman
Maya Mouler
MM
Wenzel
Valeska
V
Boergermann
Jan H
JH
Hassel
Sylke
S
Henis
Yoav I
YI
Knaus
Petra
P
D000818:Animals; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000378:metabolism*; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics / Q000378:metabolism*; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D021941:Caveolae / Q000378:metabolism; D051242:Caveolin 1 / Q000378:metabolism; D002460:Cell Line; D002522:Chlorocebus aethiops; D002784:Cholesterol / Q000378:metabolism; D004705:Endocytosis; D014644:Genetic Variation / Q000235:genetics; D006801:Humans; D051379:Mice; D008854:Microscopy, Electron; D009154:Mutation / Q000235:genetics; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D012326:RNA Splicing; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism
D019485:Bone Morphogenetic Proteins; D002135:Calcium-Binding Proteins; C495541:Cav1 protein, mouse; D051242:Caveolin 1; D010750:Phosphoproteins; D051785:Smad Proteins; D002784:Cholesterol; D052005:Bone Morphogenetic Protein Receptors, Type I; D052006:Bone Morphogenetic Protein Receptors, Type II