A GPI-linked protein that interacts with Ret to form a candidate neurturin receptor

Robert D. Klein, Daniel Sherman, Wei-Hsien Ho, Donna Stone, Gregory L. Bennett, Barbara Moffat, Richard Vandlen, Laura Simmons, Qimin Gu, Jo-Anne Hongo, Brigitte Devaux, Kris Poulsen, Mark Armanini, Chika Nozaki, Naoya Asai, Audrey Goddard, Heidi Phillips, Chris E. Henderson, Masahide Takahashi and Arnon Rosenthal ()
Additional contact information
Robert D. Klein: Genentech, Inc.
Daniel Sherman: Genentech, Inc.
Wei-Hsien Ho: Genentech, Inc.
Donna Stone: Genentech, Inc.
Gregory L. Bennett: Genentech, Inc.
Barbara Moffat: Genentech, Inc.
Richard Vandlen: Genentech, Inc.
Laura Simmons: Genentech, Inc., 460 Point San Bruno Boulevard
Qimin Gu: #INSERM U.382, Developmental Biology Institute of Marseille
Jo-Anne Hongo: Genentech, Inc.
Brigitte Devaux: Genentech, Inc.
Kris Poulsen: Genentech, Inc.
Mark Armanini: Genentech, Inc.
Chika Nozaki: Nagoya University School of Medicine
Naoya Asai: Nagoya University School of Medicine
Audrey Goddard: #INSERM U.382, Developmental Biology Institute of Marseille
Heidi Phillips: Genentech, Inc.
Chris E. Henderson: #INSERM U.382, Developmental Biology Institute of Marseille
Masahide Takahashi: Nagoya University School of Medicine
Arnon Rosenthal: Genentech, Inc.

Nature, 1997, vol. 387, issue 6634, 717-721

Abstract: Abstract Glial-cell-line-derived neurotrophic factor (GDNF) and neurturin (NTN) are two structurally related, potent survival factors for sympathetic, sensory and central nervous system neurons1,2,3,4,5,6. GDNF mediates its actions through a multicomponent receptor system composed of a ligand-binding glycosyl-phosphatidylinositol (GPI)-linked protein (designated GDNFR-α) and the transmembrane protein tyrosine kinase Ret7,8,9,10,11,12. In contrast, the mechanism by which the NTN signal is transmitted is not well understood. Here we describe the identification and tissue distribution of a GPI-linked protein (designated NTNR-α) that is structurally related to GDNFR-α. We further demonstrate that NTNR-α binds NTN (Kd ∼ 10 pM) but not GDNF with high affinity; that GDNFR-α binds to GDNF but not NTN with high affinity; and that cellular responses to NTN require the presence of NTNR-α. Finally, we show that NTN, in the presence of NTNR-α, induces tyrosine-phosphorylation of Ret, and that NTN, NTNR-α and Ret form a physical complex on the cell surface. These findings identify Ret and NTNR-α as signalling and ligand-binding components, respectively, of a receptor for NTN and define a novel family of receptors for neurotrophic and differentiation factors composed of a shared transmembrane protein tyrosine kinase and a ligand-specific GPI-linked protein.

Date: 1997
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DOI: 10.1038/42722

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