title: Of proneurotrophins and their antineurotrophic effects.
abstract: Neurotrophins perform essential processes throughout neural development. They signal through Trk receptor proteins, typically in association with a "low affinity" p75(NTR) pan-neurotrophin co-receptor. Neurotrophins are synthesized as proproteins; the pro domains are removed proteolytically to yield the mature, presumably functional forms of the neurotrophins. Recent findings, however, have revealed a positive role for the proneurotrophins themselves. The proproteins bind with high affinity to the p75(NTR) pan-neurotrophin receptor in the absence of Trks to initiate a separate set of signaling cascades that actively oppose the effects of the mature growth factors. These experiments suggest that the balance between pro- and mature neurotrophin plays a critical role in tuning downstream signaling. This view changes the neurotrophin field substantially and also points to the broader idea that the potential activities of precursor proteins deserve a closer look.
authors: National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20854, USA.
authors: Lucy
authors: L
authors: Kotlyanskaya
authors: Kristina A
authors: KA
authors: McLinden
authors: Edward
authors: E
authors: Giniger
mesh_terms: D000818:Animals; D006801:Humans; D051379:Mice; D009414:Nerve Growth Factors / Q000502:physiology*
chemical_list: D009414:Nerve Growth Factors
references: Dev Cell. 2006 Sep;11(3):313-23
references: 16950123
references: Genes Dev. 1996 Nov 15;10(22):2922-34
references: 8918893
references: Development. 2003 Oct;130(19):4673-82
references: 12925593
references: EMBO J. 1999 Feb 1;18(3):616-22
references: 9927421
references: Nature. 2004 Feb 26;427(6977):843-8
references: 14985763
references: Neuron. 1997 May;18(5):767-78
references: 9182801
references: Development. 1999 Feb;126(4):683-90
references: 9895316
references: Nature. 1996 Oct 24;383(6602):716-9
references: 8878481
references: Curr Opin Neurobiol. 1999 Feb;9(1):105-9
references: 10072368
references: Science. 2001 Nov 30;294(5548):1945-8
references: 11729324
references: Mol Cell Neurosci. 2010 Oct;45(2):108-20
references: 20584617
references: Proc Natl Acad Sci U S A. 2012 Sep 25;109(39):15924-9
references: 23019376
references: J Cell Biol. 2012 Mar 19;196(6):775-88
references: 22412021
references: J Neurosci. 2010 Oct 20;30(42):14059-67
references: 20962227
references: Annu Rev Neurosci. 2001;24:677-736
references: 11520916
references: Sci Signal. 2011 Dec 06;4(202):ra82
references: 22155786
references: Nat Rev Neurosci. 2005 Aug;6(8):603-14
references: 16062169
references: Neurotox Res. 2009 Oct;16(3):255-60
references: 19526280
references: Annu Rev Biochem. 2003;72:609-42
references: 12676795
references: J Cell Biol. 2009 May 18;185(4):727-41
references: 19451278
references: J Neurocytol. 2003 Jun-Sep;32(5-8):777-94
references: 15034267
references: Genes Dev. 1994 Jul 1;8(13):1489-501
references: 7958834