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Two growth factor signalling pathways in fibroblasts distinguished by pertussis toxin
Nature
|April 23, 1987
Summary
Mitogens activate cell growth through polyphosphoinositide hydrolysis or alternative pathways. Pertussis toxin blocks the former, confirming distinct signaling routes for cell proliferation and DNA synthesis.
Area of Science:
- Cell biology
- Molecular signaling
- Biochemistry
Background:
- Mitogens like bombesin and thrombin activate polyphosphoinositide hydrolysis via phospholipase C.
- This pathway involves G-proteins sensitive to Bordetella pertussis toxin.
- Growth factors such as EGF, FGF, and insulin/IGF-I activate receptor tyrosine kinases and can trigger DNA synthesis independently of polyphosphoinositide hydrolysis.
Purpose of the Study:
- To investigate the role of phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) hydrolysis in initiating DNA replication.
- To determine if the G-protein coupled pathway is essential for mitogenesis.
- To confirm the existence of alternative growth factor signaling pathways.
Main Methods:
- Utilized Chinese hamster lung fibroblasts, which respond to both classes of mitogens.
- Assessed the effect of pertussis toxin on thrombin-, EGF-, and FGF-induced DNA synthesis and proliferation.
- Measured inhibition of mitogenicity and DNA synthesis.
Main Results:
- Pertussis toxin inhibited thrombin-induced mitogenicity by up to 95%.
- EGF- and FGF-induced DNA synthesis and proliferation were unaffected by pertussis toxin.
- This demonstrates that thrombin-induced signaling relies on a pertussis toxin-sensitive G-protein pathway.
Conclusions:
- Activation of PtdIns(4,5)P2-phospholipase C plays a critical role in cell growth control.
- Confirmed the existence of distinct, parallel growth factor signaling pathways.
- Signaling pathways independent of polyphosphoinositide breakdown are crucial for cell proliferation.