PMID- 14696090
OWN - NLM
STAT- MEDLINE
DCOM- 20040224
LR  - 20181130
IS  - 0020-7136 (Print)
IS  - 0020-7136 (Linking)
VI  - 108
IP  - 5
DP  - 2004 Feb 20
TI  - Expression of a naturally occurring constitutively active variant of the 
      epidermal growth factor receptor in mouse fibroblasts increases motility.
PG  - 643-53
AB  - Tumor cell motility is one of the rate-limiting steps of invasion, which defines 
      progression toward a more malignant phenotype. Elevated expression of epidermal 
      growth factor receptor (EGFR) in many cancers is associated with progression of 
      superficial to invasive forms of the disease. The naturally occuring type III 
      mutant epidermal growth factor receptor (EGFRvIII) is a tumor-specific, 
      ligand-independent, constitutively active variant of the epidermal growth factor 
      receptor. EGFRvIII is expressed frequently by a number of human solid tumours 
      including those of the lung, breast, prostate, brain and ovary. Our study was 
      designed to investigate the effect of EGFRvIII expression on cell motility and 
      compare it to that of ligand-activated EGFR using transfected fibroblasts. We 
      show here using time-lapse video recording that expression of EGFRvIII greatly 
      enhances the motility of fibroblasts independently of ligand stimulation. In 
      addition, expression of EGFRvIII caused a marked increase in the number of 
      cellular protrusions (lamellipodia) and a reduction in the number of stress 
      fibers and focal adhesions. The EGFR tyrosine kinase inhibitor, AG1478, and the 
      MEK inhibitor, U0126, blocked these cellular effects of EGFRvIII. Two cell lines 
      expressing different levels of EGFR were used for comparison. The low-expressing 
      cell line responded to EGF treatment by increasing motility in a manner very 
      similar to the motility induced by EGFRvIII. In contrast, the high-expressing 
      cell line responded to EGF by detachment from the extracellular matrix and 
      decreased motility. Cellular detachment was correlated to a high phosphorylation 
      of PLC-gamma, whereas increased motility was correlated to a high level of ERK 
      phosphorylation. Overall these results indicate that tumor-associated EGFR 
      mutations might be critical for tumor cell motility, invasion and thus 
      progression of disease.
CI  - Copyright 2003 Wiley-Liss, Inc.
FAU - Pedersen, Mikkel W
AU  - Pedersen MW
AD  - Department of Radiation Biology, The Finsen Center, Copenhagen University 
      Hospital, Copenhagen, Denmark.
FAU - Tkach, Vadim
AU  - Tkach V
FAU - Pedersen, Nina
AU  - Pedersen N
FAU - Berezin, Vladimir
AU  - Berezin V
FAU - Poulsen, Hans S
AU  - Poulsen HS
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Int J Cancer
JT  - International journal of cancer
JID - 0042124
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Quinazolines)
RN  - 0 (Tyrphostins)
RN  - 0 (epidermal growth factor receptor VIII)
RN  - 170449-18-0 (RTKI cpd)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases)
RN  - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases)
RN  - EC 3.1.4.- (Type C Phospholipases)
RN  - EC 3.1.4.3 (Phospholipase C gamma)
SB  - IM
MH  - 3T3 Cells
MH  - Animals
MH  - Cell Adhesion/drug effects
MH  - Cell Movement
MH  - Enzyme Inhibitors/pharmacology
MH  - ErbB Receptors/metabolism/*physiology
MH  - Fibroblasts
MH  - Glioblastoma/metabolism
MH  - Mice
MH  - Mitogen-Activated Protein Kinase Kinases/metabolism
MH  - Models, Biological
MH  - Phospholipase C gamma
MH  - Phosphorylation
MH  - Protein-Tyrosine Kinases/metabolism
MH  - Quinazolines
MH  - Receptor Protein-Tyrosine Kinases/metabolism
MH  - Tumor Cells, Cultured
MH  - Type C Phospholipases/metabolism
MH  - Tyrphostins/pharmacology
EDAT- 2003/12/30 05:00
MHDA- 2004/02/26 05:00
CRDT- 2003/12/30 05:00
PHST- 2003/12/30 05:00 [pubmed]
PHST- 2004/02/26 05:00 [medline]
PHST- 2003/12/30 05:00 [entrez]
AID - 10.1002/ijc.11566 [doi]
PST - ppublish
SO  - Int J Cancer. 2004 Feb 20;108(5):643-53. doi: 10.1002/ijc.11566.