Distinct usages of phospholipase C gamma and Shc in intracellular signaling stimulated by neurotrophins.
Nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), members of the neurotrophin family, bind to and activate TrkA, TrkB and TrkC, respectively, members of the Trk receptor tyrosine kinase family, to exert various effects including promotion of differentiation and survival, and regulation of synaptic plasticity in neuronal cells. Many reports have suggested that different neurotrophins show distinct biological functions, although molecular mechanisms by which neurotrophins exert their different functions remain unclear. In the present study, we found distinct usages of phospholipase Cgamma (PLCgamma) and Shc in intracellular signaling stimulated by neurotrophins. BDNF stimulated much stronger interactions of PLCgamma with Trk than NGF and NT-3 in PC12 cells stably expressing TrkB and cultured cerebral cortical neurons, respectively, although BDNF, NGF and NT-3 induced similar levels of tyrosine phosphorylation of Trk. Furthermore, the cultured cortical neurons showed large PLCgamma-dependent increases in intracellular Ca(2+) levels in response to BDNF compared with NT-3. In Shc signaling, NGF, but not BDNF, displayed interactions between Trk and Shc in a phenylarsine oxide (PAO; an inhibitor of tyrosine phosphatase)-dependent manner in TrkB-expressing PC12 cells. These results indicated that neurotrophins stimulate distinct kinds of interactions between Trk and PLCgamma and between Trk and Shc. These differences may lead to the distinct biological functions of neurotrophins.
Yamada
Masashi
M
Division of Protein Biosynthesis, Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka 565-0871, Japan. yamada@protein.osaka-u.ac.jp
Numakawa
Tadahiro
T
Koshimizu
Hisatsugu
H
Tanabe
Keiko
K
Wada
Kazuyo
K
Koizumi
Shinichi
S
Hatanaka
Hiroshi
H
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D004622:Embryo, Mammalian; D005260:Female; D007424:Intracellular Fluid / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D007527:Isoenzymes / Q000502:physiology*; D008297:Male; D009414:Nerve Growth Factors / Q000494:pharmacology* / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D016716:PC12 Cells; D051966:Phospholipase C gamma; D011506:Proteins / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D020813:Receptor, trkB / Q000096:biosynthesis / Q000235:genetics; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D010738:Type C Phospholipases / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D007527:Isoenzymes; D009414:Nerve Growth Factors; D011506:Proteins; D055765:Shc Signaling Adaptor Proteins; C528035:Shc1 protein, rat; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D020813:Receptor, trkB; D010738:Type C Phospholipases; D051966:Phospholipase C gamma