PMID- 10467403
OWN - NLM
STAT- MEDLINE
DCOM- 19991004
LR  - 20211203
IS  - 0950-9232 (Print)
IS  - 0950-9232 (Linking)
VI  - 18
IP  - 32
DP  - 1999 Aug 12
TI  - The selective and inducible activation of endogenous PI 3-kinase in PC12 cells 
      results in efficient NGF-mediated survival but defective neurite outgrowth.
PG  - 4586-97
AB  - The Trk/Nerve Growth Factor receptor mediates the rapid activation of a number of 
      intracellular signaling proteins, including phosphatidylinositol 3-kinase (PI 
      3-kinase). Here, we describe a novel, NGF-inducible system that we used to 
      specifically address the signaling potential of endogenous PI 3-kinase in 
      NGF-mediated neuronal survival and differentiation processes. This system 
      utilizes a Trk receptor mutant (Trk(def)) lacking sequences Y490, Y785 and KFG 
      important for the activation of the major Trk targets; SHC, PLC-gammal, Ras, PI 
      3-kinase and SNT. Trk(def) was kinase active but defective for NGF-induced 
      responses when stably expressed in PC12nnr5 cells (which lack detectable levels 
      of TrkA and are non-responsive to NGF). The PI 3-kinase consensus binding site, 
      YxxM (YVPM), was introduced into the insert region within the kinase domain of 
      Trk(def). NGF-stimulated tyrosine phosphorylation of the Trk(def)+PI 3-kinase 
      addback receptor, resulted in the direct association and selective activation of 
      PI 3-kinase in vitro and the production of PI(3,4)P2 and PI(3,4,5)P3 in vivo 
      (comparable to wild-type). PC12nnr5 cells stably expressing Trk(def) + PI 
      3-kinase, initiated neurite outgrowth but failed to stably extend and maintain 
      these neurites in response to NGF as compared to PC12 parental cells, or PC12nnr5 
      cells overexpressing wild-type Trk. However, Trk(def) + PI 3-kinase was fully 
      competent in mediating NGF-induced survival processes. We propose that while 
      endogenous PI 3-kinase can contribute in part to neurite initiation processes, 
      its selective activation and subsequent signaling to downstream effectors such as 
      Akt, functions mainly to promote cell survival in the PC12 system.
FAU - Ashcroft, M
AU  - Ashcroft M
AD  - ABL-Basic Research Program, NCI-FCRDC, West 7th Street, Frederick, Maryland, MD 
      21702, USA.
FAU - Stephens, R M
AU  - Stephens RM
FAU - Hallberg, B
AU  - Hallberg B
FAU - Downward, J
AU  - Downward J
FAU - Kaplan, D R
AU  - Kaplan DR
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Adaptor Proteins, Vesicular Transport)
RN  - 0 (Isoenzymes)
RN  - 0 (Nerve Growth Factors)
RN  - 0 (Proteins)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Receptors, Nerve Growth Factor)
RN  - 0 (SHC1 protein, human)
RN  - 0 (Shc Signaling Adaptor Proteins)
RN  - 0 (Shc1 protein, rat)
RN  - 0 (Src Homology 2 Domain-Containing, Transforming Protein 1)
RN  - 42HK56048U (Tyrosine)
RN  - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases)
RN  - EC 2.7.10.1 (Receptor, trkA)
RN  - EC 2.7.11.1 (AKT1 protein, human)
RN  - EC 2.7.11.1 (Akt1 protein, rat)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinases)
RN  - EC 3.1.4.- (Type C Phospholipases)
RN  - EC 3.1.4.3 (Phospholipase C gamma)
SB  - IM
MH  - *Adaptor Proteins, Signal Transducing
MH  - *Adaptor Proteins, Vesicular Transport
MH  - Animals
MH  - Calcium-Calmodulin-Dependent Protein Kinases/metabolism
MH  - Cell Division
MH  - Cell Survival
MH  - Enzyme Activation
MH  - Humans
MH  - Isoenzymes/metabolism
MH  - Nerve Growth Factors/*metabolism/pharmacology
MH  - Neurites/*metabolism
MH  - Neurons/*cytology/*enzymology/metabolism
MH  - PC12 Cells
MH  - Phosphatidylinositol 3-Kinases/*metabolism
MH  - Phospholipase C gamma
MH  - Phosphorylation
MH  - *Protein Serine-Threonine Kinases
MH  - Proteins/metabolism
MH  - Proto-Oncogene Proteins/genetics/metabolism
MH  - Proto-Oncogene Proteins c-akt
MH  - Rats
MH  - Receptor Protein-Tyrosine Kinases/genetics/metabolism
MH  - Receptor, trkA
MH  - Receptors, Nerve Growth Factor/genetics/metabolism
MH  - Shc Signaling Adaptor Proteins
MH  - Src Homology 2 Domain-Containing, Transforming Protein 1
MH  - Type C Phospholipases/metabolism
MH  - Tyrosine/metabolism
EDAT- 1999/09/01 00:00
MHDA- 1999/09/01 00:01
CRDT- 1999/09/01 00:00
PHST- 1999/09/01 00:00 [pubmed]
PHST- 1999/09/01 00:01 [medline]
PHST- 1999/09/01 00:00 [entrez]
AID - 10.1038/sj.onc.1202814 [doi]
PST - ppublish
SO  - Oncogene. 1999 Aug 12;18(32):4586-97. doi: 10.1038/sj.onc.1202814.