Repulsive guidance molecule RGMa alters utilization of bone morphogenetic protein (BMP) type II receptors by BMP2 and BMP4.
Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-beta superfamily of multifunctional ligands that transduce their signals through type I and II serine/threonine kinase receptors and intracellular Smad proteins. Recently, we identified the glycosylphosphatidylinositol-anchored repulsive guidance molecules RGMa, DRAGON (RGMb), and hemojuvelin (RGMc) as coreceptors for BMP signaling (Babbit, J. L., Huang, F. W., Wrighting, D. W., Xia, Y., Sidis, Y., Samad, T. A., Campagna, J. A., Chung, R., Schneyer, A., Woolf, C. J., Andrews, N. C., and Lin, H. Y. (2006) Nat. Genet. 38, 531-539; Babbit, J. L., Zhang, Y., Samad, T. A., Xia, Y., Tang, J., Schneyer, A., Woolf, C. J., and Lin, H. Y. (2005) J. Biol. Chem. 280, 29820-29827; Samad, T. A., Rebbapragada, A., Bell, E., Zhang, Y., Sidis, Y., Jeong, S. J., Campagna, J. A., Perusini, S., Fabrizio, D. A., Schneyer, A. L., Lin, H. Y., Brivanlou, A. H., Attisano, L., and Woolf, C. J. (2005) J. Biol. Chem. 280, 14122-14129). However, the mechanism by which RGM family members enhance BMP signaling remains unknown. Here, we report that RGMa bound to radiolabeled BMP2 and BMP4 with Kd values of 2.4+/-0.2 and 1.4+/-0.1 nm, respectively. In KGN human ovarian granulosa cells and mouse pulmonary artery smooth muscle cells, BMP2 and BMP4 signaling required BMP receptor type II (BMPRII), but not activin receptor type IIA (ActRIIA) or ActRIIB, based on changes in BMP signaling by small interfering RNA inhibition of receptor expression. In contrast, cells transfected with RGMa utilized both BMPRII and ActRIIA for BMP2 or BMP4 signaling. Furthermore, in BmpRII-null pulmonary artery smooth muscle cells, BMP2 and BMP4 signaling was reduced by inhibition of endogenous RGMa expression, and RGMa-mediated BMP signaling required ActRIIA expression. These findings suggest that RGMa facilitates the use of ActRIIA by endogenous BMP2 and BMP4 ligands that otherwise prefer signaling via BMPRII and that increased utilization of ActRIIA leads to generation of an enhanced BMP signal.
Xia
Yin
Y
Program in Membrane Biology and the Division of Nephrology, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02114.
Yu
Paul B
PB
Cardiovascular Research Center, Harvard Medical School, Boston, Massachusetts 02114.
Sidis
Yisrael
Y
Reproductive Endocrine Unit, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02114.
Beppu
Hideyuki
H
Cardiovascular Research Center, Harvard Medical School, Boston, Massachusetts 02114.
Bloch
Kenneth D
KD
Cardiovascular Research Center, Harvard Medical School, Boston, Massachusetts 02114; Department of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114.
Schneyer
Alan L
AL
Reproductive Endocrine Unit, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02114.
Lin
Herbert Y
HY
Program in Membrane Biology and the Division of Nephrology, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02114. Electronic address: hlin@partners.org.
D030301:Activin Receptors, Type II / Q000502:physiology*; D000818:Animals; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000378:metabolism*; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D005260:Female; D058851:GPI-Linked Proteins; D006107:Granulosa Cells / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D009130:Muscle, Smooth / Q000166:cytology; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*
C525718:BMP2 protein, human; C525809:BMP4 protein, human; C525719:Bmp2 protein, mouse; C525810:Bmp4 protein, mouse; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D058851:GPI-Linked Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C522183:RGMA protein, human; C483496:Rgma protein, mouse; D016212:Transforming Growth Factor beta; D030301:Activin Receptors, Type II; D052006:Bone Morphogenetic Protein Receptors, Type II; C425585:activin receptor type II-A