p75 nerve growth factor receptor modulates p140trkA kinase activity, but not ligand internalization, in PC12 cells
✍ Scribed by P. Kahle; P. A. Barker; E. M. Shooter; C. Hertel
- Publisher
- John Wiley and Sons
- Year
- 1994
- Tongue
- English
- Weight
- 799 KB
- Volume
- 38
- Category
- Article
- ISSN
- 0360-4012
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✦ Synopsis
Abstract
The biological activity of nerve growth factor (NGF) has been shown to be mediated by the p140^__trk__A^ receptor tyrosine kinase, while the role of the p75 NGF receptor (p75^NGFR^) is still unresolved. Here we have investigated the relative contribution of p140^__trk__A^ and p75^NGFR^ to early consequences of NGF binding: ligand internalization, p140^__trk__A^ autophosphorylation, and tyrosine phosphorylation of Shc, phospholipase C~γ‐1~ (PLC~γ‐1~), and extracellular signal‐regulated kinases (ERKs). It was found that NGF internalization was neither prevented by blocking p140^__trk__A^ activity using the protein kinase inhibitors methylthioadenosine, staurosporine, and K‐252a, nor by inhibiting NGF binding to p75^NGFR^ with antibodies. However, when NGF binding to p140^__trk__A^ was reduced by the use of a synthetic peptide corresponding to amino acids 36–53 of human p140^__trk__A^, internalization of NGF was decreased. Thus, at least in PC12 cells, internalization appears to require binding of NGF to p140^__trk__A^, but occurs irrespective of p140^__trk__A^ kinase activity and ligand occupancy of p75^NGFR^. The NGF triple mutant Lys‐32/Lys‐34/Glu‐35 to Ala, which has been demonstrated to bind to p140^__trk__A^, but not to p75^NGFR^, induced tyrosine phosphorylation more rapidly than wild‐type NGF. Likewise, NGF‐induced tyrosine phosphorylation was accelerated when NGF binding to p75^NGFR^ was prevented with REX‐IgG. These findings indicate that NGF binding by p75^NGFR^ may modulate NGF‐induced p140^__trk__A^ kinase activity. © 1994 Wiley‐Liss, Inc.