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- Title
Trk-dependent ADAM17 activation facilitates neurotrophin survival signaling.
- Authors
Kommaddi, Reddy P.; Thomas, Rhalena; Ceni, Claire; Daigneault, Kathleen; Barker, Philip A.
- Abstract
Signaling by TrkA and TrkB receptor tyrosine kinase is required for peripheral neuron survival. TrkA and TrkB signaling is facilitated by the p75 neurotrophin receptor (p75NTR), a member of the tumor necrosis factor (TNF) receptor superfamily, through mechanisms that remain obscure. Here, we demonstrate that TrkA and TrkB induces MEK-dependent phosphorylation of the transmembrane cysteine protease ADAM17 (a disintegrin and metal-loprotease 17) at the intracellular residue threonine 735. Phosphorylation at this site activates ADAM17 and causes cleavage of p75NTR and production of ICD the receptors' intracellular domain (p75NTRICD PC12 cells and in primary cerebellar granule neurons. We show that Trk-induced ADAM17 phosphor-ylation and generation of the p75NTR is required for neurotrophin-induced Erk and Akt activation and for neurotrophin-dependent survival signaling. Sur- vival of PC12 cells maintained in 10 ng/ml nerve growth factor drops by 47% in cells depleted of ADAM17; this survival deficit is resolved if the p75NTRICD is overexpressed in the ADAM17 depleted cells. These studies identify a novel signaling circuit in which Trk activates ADAM17-dependent p75NTRICD production to feedback to sustain Trk signaling and Trk-dependent survival.
- Subjects
NEUROTROPHINS; TUMOR necrosis factors; CYSTEINE proteinases; NEURONS; PHOSPHORYLATION
- Publication
FASEB Journal, 2011, Vol 25, Issue 6, p2061
- ISSN
0892-6638
- Publication type
Article
- DOI
10.1096/fj.10-173740