PMID- 16573649 OWN - NLM STAT- MEDLINE DCOM- 20060622 LR - 20131121 IS - 0022-3042 (Print) IS - 0022-3042 (Linking) VI - 97 IP - 3 DP - 2006 May TI - The protein tyrosine phosphatase, Shp2, is required for the complete activation of the RAS/MAPK pathway by brain-derived neurotrophic factor. PG - 834-45 AB - Brain-derived neurotrophic factor (BDNF) and other neurotrophins induce a unique prolonged activation of mitogen-activated protein kinase (MAPK) compared with growth factors. Characterization and kinetic and spatial modeling of the signaling pathways underlying this prolonged MAPK activation by BDNF will be important in understanding the physiological role of BDNF in many complex systems in the nervous system. In addition to Shc, fibroblast growth factor receptor substrate 2 (FRS2) is required for the BDNF-induced activation of MAPK. BDNF induces phosphorylation of FRS2. However, BDNF does not induce phosphorylation of FRS2 in cells expressing a deletion mutant of TrkB (TrkBDeltaPTB) missing the juxtamembrane NPXY motif. This motif is the binding site for SHC. NPXY is the consensus sequence for phosphotyrosine binding (PTB) domains, and notably, FRS2 and SHC contain PTB domains. This NPXY motif, which contains tyrosine 484 of TrkB, is therefore the binding site for both FRS2 and SHC. Moreover, the proline containing region (VIENP) of the NPXY motif is also required for FRS2 and SHC phosphorylation, which indicates this region is an important component of FRS2 and SHC recognition by TrkB. Previously, we had found that the phosphorylation of FRS2 induces association of FRS2 and growth factor receptor binding protein 2 (Grb2). Now, we have intriguing data that indicates BDNF induces association of the SH2 domain containing protein tyrosine phosphatase, Shp2, with FRS2. Moreover, the PTB association motif of TrkB containing tyrosine 484 is required for the BDNF-induced association of Shp2 with FRS2 and the phosphorylation of Shp2. These results imply that FRS2 and Shp2 are in a BDNF signaling pathway. Shp2 is required for complete MAPK activation by BDNF, as expression of a dominant negative Shp2 in cells attenuates BDNF-induced activation of MAPK. Moreover, expression of a dominant negative Shp2 attenuates Ras activation showing that the protein tyrosine phosphatase is required for complete activation of MAPKs by BDNF. In conclusion, Shp2 regulates BDNF signaling through the MAPK pathway by regulating either Ras directly or alternatively, by signaling components upstream of Ras. Characterization of MAPK signaling controlled by BDNF is likely to be required to understand the complex physiological role of BDNF in neuronal systems ranging from the regulation of neuronal growth and survival to the regulation of synapses. FAU - Easton, John B AU - Easton JB AD - Department of Molecular Pharmacology, St Jude Children's Research Hospital, North Lauderdale, Memphis, Tennessee, USA. FAU - Royer, Amanda R AU - Royer AR FAU - Middlemas, David S AU - Middlemas DS LA - eng GR - CA 21765/CA/NCI NIH HHS/United States GR - CA 71628/CA/NCI NIH HHS/United States PT - Comparative Study PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20060329 PL - England TA - J Neurochem JT - Journal of neurochemistry JID - 2985190R RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Intracellular Signaling Peptides and Proteins) RN - 147336-22-9 (Green Fluorescent Proteins) RN - 42HK56048U (Tyrosine) RN - EC 2.7.10.1 (Receptor, trkB) RN - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases) RN - EC 3.1.3.48 (PTPN11 protein, human) RN - EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 11) RN - EC 3.1.3.48 (Protein Tyrosine Phosphatases) RN - EC 3.1.3.48 (Ptpn11 protein, rat) RN - EC 3.1.3.48 (SH2 Domain-Containing Protein Tyrosine Phosphatases) RN - EC 3.6.5.2 (ras Proteins) SB - IM MH - Amino Acid Motifs/physiology MH - Animals MH - Animals, Newborn MH - Blotting, Western/methods MH - Brain-Derived Neurotrophic Factor/*pharmacology MH - Cells, Cultured MH - Cerebral Cortex/cytology MH - Enzyme Activation/drug effects MH - Green Fluorescent Proteins/genetics/metabolism MH - Humans MH - Immunoprecipitation/methods MH - Intracellular Signaling Peptides and Proteins/*physiology MH - Mitogen-Activated Protein Kinase Kinases/*metabolism MH - Mutagenesis, Site-Directed/methods MH - Neuroblastoma MH - Neurons/*drug effects/metabolism MH - Protein Tyrosine Phosphatase, Non-Receptor Type 11 MH - Protein Tyrosine Phosphatases/*physiology MH - Rats MH - Rats, Long-Evans MH - Receptor, trkB/metabolism MH - SH2 Domain-Containing Protein Tyrosine Phosphatases MH - Signal Transduction/*drug effects MH - Time Factors MH - Transfection/methods MH - Tyrosine/metabolism MH - ras Proteins/*metabolism EDAT- 2006/04/01 09:00 MHDA- 2006/06/23 09:00 CRDT- 2006/04/01 09:00 PHST- 2006/04/01 09:00 [pubmed] PHST- 2006/06/23 09:00 [medline] PHST- 2006/04/01 09:00 [entrez] AID - JNC3789 [pii] AID - 10.1111/j.1471-4159.2006.03789.x [doi] PST - ppublish SO - J Neurochem. 2006 May;97(3):834-45. doi: 10.1111/j.1471-4159.2006.03789.x. Epub 2006 Mar 29.