PMID- 10648629
OWN - NLM
STAT- MEDLINE
DCOM- 20000215
LR  - 20190508
IS  - 0270-7306 (Print)
IS  - 0270-7306 (Linking)
VI  - 20
IP  - 4
DP  - 2000 Feb
TI  - A novel positive feedback loop mediated by the docking protein Gab1 and
      phosphatidylinositol 3-kinase in epidermal growth factor receptor signaling.
PG  - 1448-59
AB  - The Gab1 protein is tyrosine phosphorylated in response to various growth factors
      and serves as a docking protein that recruits a number of downstream signaling
      proteins, including phosphatidylinositol 3-kinase (PI-3 kinase). To determine the
      role of Gab1 in signaling via the epidermal growth factor (EGF) receptor (EGFR)
      we tested the ability of Gab1 to associate with and modulate signaling by this
      receptor. We show that Gab1 associates with the EGFR in vivo and in vitro via
      pTyr sites 1068 and 1086 in the carboxy-terminal tail of the receptor and that
      overexpression of Gab1 potentiates EGF-induced activation of the
      mitogen-activated protein kinase and Jun kinase signaling pathways. A mutant of
      Gab1 unable to bind the p85 subunit of PI-3 kinase is defective in potentiating
      EGFR signaling, confirming a role for PI-3 kinase as a downstream effector of
      Gab1. Inhibition of PI-3 kinase by a dominant-interfering mutant of p85 or by
      Wortmannin treatment similarly impairs Gab1-induced enhancement of signaling via 
      the EGFR. The PH domain of Gab1 was shown to bind specifically to
      phosphatidylinositol 3,4,5-triphosphate [PtdIns(3,4,5)P3], a product of PI-3
      kinase, and is required for activation of Gab1-mediated enhancement of EGFR
      signaling. Moreover, the PH domain mediates Gab1 translocation to the plasma
      membrane in response to EGF and is required for efficient tyrosine
      phosphorylation of Gab1 upon EGF stimulation. In addition, overexpression of Gab1
      PH domain blocks Gab1 potentiation of EGFR signaling. Finally, expression of the 
      gene for the lipid phosphatase PTEN, which dephosphorylates PtdIns(3,4, 5)P3,
      inhibits EGF signaling and translocation of Gab1 to the plasma membrane. These
      results reveal a novel positive feedback loop, modulated by PTEN, in which PI-3
      kinase functions as both an upstream regulator and a downstream effector of Gab1 
      in signaling via the EGFR.
FAU - Rodrigues, G A
AU  - Rodrigues GA
AD  - Department of Pharmacology and Skirball Institute, New York University Medical
      Center, New York, New York 10016, USA.
FAU - Falasca, M
AU  - Falasca M
FAU - Zhang, Z
AU  - Zhang Z
FAU - Ong, S H
AU  - Ong SH
FAU - Schlessinger, J
AU  - Schlessinger J
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Mol Cell Biol
JT  - Molecular and cellular biology
JID - 8109087
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (GAB1 protein, human)
RN  - 0 (Phosphatidylinositol Phosphates)
RN  - 0 (Phosphoproteins)
RN  - 0 (Recombinant Fusion Proteins)
RN  - 0 (Tumor Suppressor Proteins)
RN  - 0 (phosphatidylinositol 3,4,5-triphosphate)
RN  - 42HK56048U (Tyrosine)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - EC 3.1.3.2 (Phosphoric Monoester Hydrolases)
RN  - EC 3.1.3.67 (PTEN Phosphohydrolase)
RN  - EC 3.1.3.67 (PTEN protein, human)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing
MH  - Animals
MH  - Biological Transport, Active
MH  - COS Cells
MH  - Cell Line
MH  - Cell Membrane/metabolism
MH  - Enzyme Activation
MH  - ErbB Receptors/chemistry/genetics/*metabolism
MH  - Feedback
MH  - HeLa Cells
MH  - Humans
MH  - JNK Mitogen-Activated Protein Kinases
MH  - Mitogen-Activated Protein Kinases/metabolism
MH  - Models, Biological
MH  - PTEN Phosphohydrolase
MH  - Phosphatidylinositol 3-Kinases/*metabolism
MH  - Phosphatidylinositol Phosphates/metabolism
MH  - Phosphoproteins/chemistry/genetics/*metabolism
MH  - Phosphoric Monoester Hydrolases/metabolism
MH  - Phosphorylation
MH  - Protein Structure, Tertiary
MH  - Recombinant Fusion Proteins/chemistry/genetics/metabolism
MH  - Signal Transduction
MH  - *Tumor Suppressor Proteins
MH  - Tyrosine/metabolism
PMC - PMC85307
EDAT- 2000/01/29 09:00
MHDA- 2000/02/19 09:00
CRDT- 2000/01/29 09:00
PHST- 2000/01/29 09:00 [pubmed]
PHST- 2000/02/19 09:00 [medline]
PHST- 2000/01/29 09:00 [entrez]
AID - 10.1128/mcb.20.4.1448-1459.2000 [doi]
PST - ppublish
SO  - Mol Cell Biol. 2000 Feb;20(4):1448-59. doi: 10.1128/mcb.20.4.1448-1459.2000.