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G protein-coupled receptors and signaling pathways regulating growth responses
1Department of Pharmacology, University of California, San Diego, La Jolla 92093, USA.
Abstract:
Hormones that interact with seven-transmembrane spanning receptors, generally considered to be involved in acute signaling functions, also induce longer term effects on gene expression and cell growth. These genetic and proliferative effects can be induced by activation of receptors that signal through heterotrimeric GTP-binding proteins (G-proteins) of the Gq family, pertussis toxin-sensitive Gi/Go proteins, Gs, or G12/G13. Numerous growth-promoting G protein-coupled receptors activate the low molecular weight G-protein Ras and stimulate mitogen-activated protein kinase. Recent data suggest that c-Jun NH2-terminal kinase is also activated, possibly through interaction with low molecular weight G-proteins of the Rho family. Because G protein-coupled receptors lack intrinsic tyrosine kinase activity, the mechanisms by which heterotrimeric G-proteins couple to these kinase cascades remain to be elucidated. By analogy to growth factor receptors, G protein-coupled receptors may access these kinase cascades through binding of adapter proteins or recruitment of cytosolic tyrosine kinases. It is likely that interactions between multiple signaling pathways are required for G protein-coupled receptors to propagate signals to the nucleus.
Insights
Hormones activating G protein-coupled receptors trigger long-term gene expression and cell growth. These pathways involve various G-protein families and kinase cascades, impacting cellular proliferation.
Area of Science:
- Cellular signaling and molecular biology
- Endocrinology and molecular mechanisms of hormone action
Background:
- Seven-transmembrane spanning receptors (GPCRs) mediate acute hormonal responses.
- GPCRs also influence long-term cellular processes like gene expression and growth.
- Diverse heterotrimeric G-proteins (Gq, Gi/Go, Gs, G12/G13) mediate GPCR signaling.
Purpose of the Study:
- To explore the mechanisms linking G protein-coupled receptors to downstream kinase cascades.
- To understand how GPCRs regulate gene expression and cell proliferation.
- To elucidate the role of small molecular weight G-proteins in GPCR signaling.
Main Methods:
- Analysis of signaling pathways involving G-proteins and mitogen-activated protein kinase (MAPK).
- Investigation of c-Jun NH2-terminal kinase (JNK) activation.
- Exploration of potential mechanisms for GPCR coupling to kinase cascades, including adapter proteins and tyrosine kinases.
Main Results:
- GPCR activation by hormones can lead to sustained gene expression and cell growth.
- Growth-promoting GPCRs activate Ras and MAPK pathways.
- Rho family G-proteins may activate JNK, and GPCRs may recruit cytosolic tyrosine kinases to link to kinase cascades.
Conclusions:
- GPCRs initiate complex signaling networks involving multiple G-protein families and kinase cascades.
- Interactions between various signaling pathways are crucial for GPCRs to transmit signals to the nucleus.
- Further research is needed to fully elucidate the mechanisms of GPCR-mediated gene expression and cell growth.