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Signal transduction in c-met mediated motogenesis
D L Faletto1, D R Kaplan, D O Halverson
1ABL-Basic Research Program, NCI-Frederick Cancer Research & Development Center, MD 21702.
Abstract:
We have begun characterizing the signal transduction pathways used by the c-met receptor in cells in which ligand (HGF-SF) stimulates motogenesis in the absence of mitogenesis. Primary targets (within 10-15 minutes) were identified as PI-3 kinase, GAP, PLC gamma, src, and MAP kinase, substrates which are also activated upon growth factor activation of mitogenic receptor systems. Following HGF-SF treatment, the 85 kD subunit of PI-3 kinase is phosphorylated on tyrosine and PI-3 kinase activity rapidly associates with the c-met receptor. A number of these substrates are implicated in cytoskeletal rearrangements and may be important in the motogenic response to the factor. We have also identified a number of colon carcinoma lines which express unamplified levels of constitutively tyrosine phosphorylated c-met protein. In these and other (gastric) cell lines which express amplified levels of activated receptor protein, we have determined that receptor activation is not due to the autocrine production of ligand.
Insights
The c-MET receptor
Area of Science:
- Cellular signaling pathways
- Receptor tyrosine kinases
- Cancer biology
Background:
- The c-MET receptor tyrosine kinase plays a role in cell motility and growth.
- Understanding c-MET signaling is crucial for cancer research, particularly in colon and gastric carcinomas.
Purpose of the Study:
- To characterize signal transduction pathways activated by HGF-SF.
- To identify primary signaling targets involved in c-MET-mediated motogenesis.
- To investigate c-MET activation mechanisms in carcinoma cell lines.
Main Methods:
- Ligand stimulation (HGF-SF) of cells expressing c-MET.
- Analysis of primary signaling targets including PI-3 kinase, GAP, PLC gamma, src, and MAP kinase.
- Assessment of tyrosine phosphorylation and kinase activity.
- Identification and characterization of colon and gastric carcinoma cell lines with varying c-MET expression.
Main Results:
- HGF-SF rapidly activates PI-3 kinase, GAP, PLC gamma, src, and MAP kinase.
- PI-3 kinase associates with c-MET and its 85 kD subunit is tyrosine phosphorylated.
- Several activated substrates are implicated in cytoskeletal rearrangements.
- Constitutively active c-MET was identified in colon carcinoma lines without ligand autocrine production.
Conclusions:
- c-MET signaling involves key pathways like PI-3 kinase and MAP kinase, crucial for motogenesis.
- Activated c-MET in carcinomas may not rely on autocrine ligand production.
- These findings offer insights into c-MET-driven cancer progression and potential therapeutic targets.