title: Constitutive negative regulation in the processing of the anti-Müllerian hormone receptor II.
abstract: The levels and intracellular localization of wild-type transforming growth factor β superfamily (TGFβ-SF) receptors are tightly regulated by endocytic trafficking, shedding and degradation. In contrast, a main regulatory mechanism of mutation-bearing receptors involves their intracellular retention. Anti-Müllerian hormone receptor II (AMHRII, also known as AMHR2) is the type-II receptor for anti-Müllerian hormone (AMH), a TGFβ-SF ligand that mediates Müllerian duct regression in males. Here, we studied AMHRII processing and identified novel mechanisms of its constitutive negative regulation. Immunoblot analysis revealed that a significant portion of AMHRII was missing most of its extracellular domain (ECD) and, although glycosylated, was unfolded and retained in the endoplasmic reticulum. Exogenous expression of AMHRII, but not of type-II TGF-β receptor (TβRII, also known as TGFR2), resulted in its disulfide-bond-mediated homo-oligomerization and intracellular retention, and in a decrease in its AMH-binding capacity. At the plasma membrane, AMHRII differed from TβRII, forming high levels of non-covalent homomeric complexes, which exhibited a clustered distribution and restricted lateral mobility. This study identifies novel mechanisms of negative regulation of a type-II TGFβ-SF receptor through cleavage, intracellular retention and/or promiscuous disulfide-bond mediated homo-oligomerization.
authors: Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel-Aviv, Israel 69978.
authors: Tal
authors: T
authors: Hirschhorn
authors: Université Paris Diderot, Sorbonne Paris Cité, Biologie Fonctionnelle et Adaptative (BFA), F-75013 Paris, France CNRS, UMR 8251, Biologie Fonctionnelle et Adaptative, F-75013 Paris, France INSERM U1133, Physiologie de l'Axe Gonadotrope, F-75013 Paris, France.
authors: Nathalie
authors: N
authors: di Clemente
authors: Department of Neurobiology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel.
authors: Ayelet R
authors: AR
authors: Amsalem
authors: Biogen-Idec, Inc., 14 Cambridge Center, Cambridge, MA 02142, USA.
authors: R Blake
authors: RB
authors: Pepinsky
authors: INSERM U1133, Physiologie de l'Axe Gonadotrope, F-75013 Paris, France.
authors: Jean-Yves
authors: JY
authors: Picard
authors: Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel-Aviv, Israel 69978.
authors: Nechama I
authors: NI
authors: Smorodinsky
authors: INSERM U1133, Physiologie de l'Axe Gonadotrope, F-75013 Paris, France Boston University, 590 Commonwealth Avenue, Boston, MA 02215, USA richcate@comcast.net marceloe@post.tau.ac.il.
authors: Richard L
authors: RL
authors: Cate
authors: Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel-Aviv, Israel 69978 richcate@comcast.net marceloe@post.tau.ac.il.
authors: Marcelo
authors: M
authors: Ehrlich
mesh_terms: D000818:Animals; D054304:Anti-Mullerian Hormone / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D051379:Mice; D011485:Protein Binding; D017510:Protein Folding; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018000:Receptors, Peptide / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018125:Receptors, Transforming Growth Factor beta / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D018000:Receptors, Peptide; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; C084621:anti-Mullerian hormone receptor; D054304:Anti-Mullerian Hormone; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II
keywords: Anti-Müllerian hormone; Disulfide bonds; Fluorescence recovery after photobleaching; Immunofluorescence co-patching; Receptor cleavage; Receptor oligomerization; TGF-β superfamily