PMID- 25159185
OWN - NLM
STAT- MEDLINE
DCOM- 20151015
LR  - 20211021
IS  - 1559-1166 (Electronic)
IS  - 0895-8696 (Linking)
VI  - 55
IP  - 3
DP  - 2015 Mar
TI  - The signaling adapter, FRS2, facilitates neuronal branching in primary cortical 
      neurons via both Grb2- and Shp2-dependent mechanisms.
PG  - 663-77
LID - 10.1007/s12031-014-0406-4 [doi]
AB  - The neurotrophins are a family of closely related growth factors that regulate 
      proliferation and differentiation in the developing and mature nervous systems. 
      Neurotrophins stimulate a family of receptor tyrosine kinases (Trk receptors) and 
      utilize an intracellular docking protein termed fibroblast growth factor (FGF) 
      receptor substrate 2 (FRS2) as a major downstream adapter to activate Ras, 
      phosphatidylinositide 3-kinase (PI3K), and mitogen-activated protein kinase 
      (MAPK) signaling cascades. The goals of this study were twofold: first, to 
      investigate the complexity of neurotrophin-induced FRS2 interactions in primary 
      cortical neurons and to determine which pathway(s) are important in regulating 
      neuronal growth and, second, to determine whether the related signaling adapter, 
      FRS3, stimulates neuron growth comparable to FRS2. We find that neurotrophin 
      treatment of primary cortical neurons stimulates the tyrosine phosphorylation of 
      FRS2 and the subsequent recruitment of Shp2, Grb2, and Gab2. With FRS2 mutants 
      deficient in Grb2 or Shp2 binding, we demonstrate that FRS2 binds Gab1 and Gab2 
      through Grb2, providing an alternative route to activate PI3 kinase and Shp2. 
      Using recombinant adenoviruses expressing FRS2, we demonstrate that FRS2 
      overexpression promotes neurite outgrowth and branching in cortical neurons 
      relative to controls. In contrast, overexpression of FRS3 does not stimulate 
      neuronal growth. Moreover, we find that while loss of Shp2, but not Grb2, reduces 
      brain-derived neurotrophic factor (BDNF)-induced MAPK activation, the loss of 
      either pathway impairs neuronal growth. Collectively, these experiments 
      demonstrate that FRS2 functions as an adapter of a multiprotein complex that is 
      activated by the Trk receptors and that the activation of both Grb2- and 
      Shp2-dependent pathways facilitates cortical neuronal growth.
FAU - Zhou, Li
AU  - Zhou L
AD  - Laboratory of Neural Signaling, Molecular Medicine Research Group, The Robarts 
      Research Institute, 1151 Richmond St. N, London, Ontario, N6A 5B7, Canada.
FAU - Talebian, Asghar
AU  - Talebian A
FAU - Meakin, Susan O
AU  - Meakin SO
LA  - eng
GR  - Canadian Institutes of Health Research/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140827
PL  - United States
TA  - J Mol Neurosci
JT  - Journal of molecular neuroscience : MN
JID - 9002991
RN  - 0 (FRS2alpha protein, mouse)
RN  - 0 (GRB2 Adaptor Protein)
RN  - 0 (Grb2 protein, mouse)
RN  - 0 (Membrane Proteins)
RN  - EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 11)
RN  - EC 3.1.3.48 (Ptpn11 protein, mouse)
SB  - IM
MH  - Animals
MH  - COS Cells
MH  - Cells, Cultured
MH  - Cerebral Cortex/cytology/*metabolism
MH  - Chlorocebus aethiops
MH  - GRB2 Adaptor Protein/genetics/*metabolism
MH  - HEK293 Cells
MH  - Humans
MH  - MAP Kinase Signaling System
MH  - Membrane Proteins/genetics/*metabolism
MH  - Mice
MH  - Neurons/cytology/*metabolism
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Protein Binding
MH  - Protein Tyrosine Phosphatase, Non-Receptor Type 11/genetics/*metabolism
EDAT- 2014/08/28 06:00
MHDA- 2015/10/16 06:00
CRDT- 2014/08/28 06:00
PHST- 2014/01/09 00:00 [received]
PHST- 2014/08/15 00:00 [accepted]
PHST- 2014/08/28 06:00 [entrez]
PHST- 2014/08/28 06:00 [pubmed]
PHST- 2015/10/16 06:00 [medline]
AID - 10.1007/s12031-014-0406-4 [doi]
PST - ppublish
SO  - J Mol Neurosci. 2015 Mar;55(3):663-77. doi: 10.1007/s12031-014-0406-4. Epub 2014 
      Aug 27.