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Activation of the c-Met receptor complex in fibroblasts drives invasive cell behavior by signaling through transcription factor STAT3

Cramer, Alexander; Kleiner, Sandra; Westermann, Martin; Meissner, Anja LU ; Lange, Anika and Friedrich, Karlheinz (2005) In Journal of Cellular Biochemistry 95(4). p.805-816
Abstract

c-Met is the receptor for hepatocyte growth factor/scatter factor (HGF/SF). It mediates multiple cellular responses in development and adult life, and c-Met hyperactivity is associated with malignant transformation of cells and the acquisition of metastatic properties. Signal transducer and activator of transcription 3 (STAT3) has been shown to contribute to c-Met-mediated cell motility and is, thus, potentially involved in the control of invasive cell behavior. We have functionally reconstituted c-Met-dependent signal transduction in fibroblasts with the aim of studying Met-driven cell invasiveness and the role of STAT3 in this phenomenon. Activation of the system was achieved by means of a hybrid receptor comprising the extracellular... (More)

c-Met is the receptor for hepatocyte growth factor/scatter factor (HGF/SF). It mediates multiple cellular responses in development and adult life, and c-Met hyperactivity is associated with malignant transformation of cells and the acquisition of metastatic properties. Signal transducer and activator of transcription 3 (STAT3) has been shown to contribute to c-Met-mediated cell motility and is, thus, potentially involved in the control of invasive cell behavior. We have functionally reconstituted c-Met-dependent signal transduction in fibroblasts with the aim of studying Met-driven cell invasiveness and the role of STAT3 in this phenomenon. Activation of the system was achieved by means of a hybrid receptor comprising the extracellular domain of the nerve growth factor (NGF) receptor TrkA, the cytoplasmic part of c-Met and a C-terminally fused blue fluorescent protein (BFP). In addition, a GFP-tagged derivative of adaptor protein Gab1 was expressed. NGF-stimulation of mouse fibroblasts expressing tagged versions of both Trk-Met and Gab1 with NGF resulted in anchorage-independent growth and enhanced invasiveness. By freeze-fracture cytochemistry and electron microscopy, we were able to visualize the ligand-induced formation of multivalent receptor complex assemblies within the cell membrane. NGF-stimulation of the heterologous receptor system evoked activation of STAT3 as evidenced by tyrosine phosphorylation and the formation of STAT3 clusters at the cell membrane. siRNA-mediated ablation of STAT3 expression resulted in a drastic reduction of c-Met-driven invasiveness, indicating an important role of STAT3 in the control of this particularly relevant property of transformed cells.

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author
publishing date
type
Contribution to journal
publication status
published
keywords
c-Met, Invasiveness, Receptor activation, STAT3
in
Journal of Cellular Biochemistry
volume
95
issue
4
pages
12 pages
publisher
Wiley-Blackwell
external identifiers
  • scopus:24744451993
ISSN
0730-2312
DOI
10.1002/jcb.20459
language
English
LU publication?
no
id
6276f079-2a08-411d-944e-f2335abc2ee2
date added to LUP
2017-05-23 22:26:51
date last changed
2017-05-24 12:10:39
@article{6276f079-2a08-411d-944e-f2335abc2ee2,
  abstract     = {<p>c-Met is the receptor for hepatocyte growth factor/scatter factor (HGF/SF). It mediates multiple cellular responses in development and adult life, and c-Met hyperactivity is associated with malignant transformation of cells and the acquisition of metastatic properties. Signal transducer and activator of transcription 3 (STAT3) has been shown to contribute to c-Met-mediated cell motility and is, thus, potentially involved in the control of invasive cell behavior. We have functionally reconstituted c-Met-dependent signal transduction in fibroblasts with the aim of studying Met-driven cell invasiveness and the role of STAT3 in this phenomenon. Activation of the system was achieved by means of a hybrid receptor comprising the extracellular domain of the nerve growth factor (NGF) receptor TrkA, the cytoplasmic part of c-Met and a C-terminally fused blue fluorescent protein (BFP). In addition, a GFP-tagged derivative of adaptor protein Gab1 was expressed. NGF-stimulation of mouse fibroblasts expressing tagged versions of both Trk-Met and Gab1 with NGF resulted in anchorage-independent growth and enhanced invasiveness. By freeze-fracture cytochemistry and electron microscopy, we were able to visualize the ligand-induced formation of multivalent receptor complex assemblies within the cell membrane. NGF-stimulation of the heterologous receptor system evoked activation of STAT3 as evidenced by tyrosine phosphorylation and the formation of STAT3 clusters at the cell membrane. siRNA-mediated ablation of STAT3 expression resulted in a drastic reduction of c-Met-driven invasiveness, indicating an important role of STAT3 in the control of this particularly relevant property of transformed cells.</p>},
  author       = {Cramer, Alexander and Kleiner, Sandra and Westermann, Martin and Meissner, Anja and Lange, Anika and Friedrich, Karlheinz},
  issn         = {0730-2312},
  keyword      = {c-Met,Invasiveness,Receptor activation,STAT3},
  language     = {eng},
  month        = {07},
  number       = {4},
  pages        = {805--816},
  publisher    = {Wiley-Blackwell},
  series       = {Journal of Cellular Biochemistry},
  title        = {Activation of the c-Met receptor complex in fibroblasts drives invasive cell behavior by signaling through transcription factor STAT3},
  url          = {http://dx.doi.org/10.1002/jcb.20459},
  volume       = {95},
  year         = {2005},
}