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Integrins regulate the linkage between upstream and downstream events in G protein-coupled receptor signaling to
S M Short1, J L Boyer, R L Juliano
1Department of Pharmacology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-7365, USA.
Abstract:
Receptor tyrosine kinases (RTKs) and G protein-coupled receptors (GPCRs) can both activate mitogen-activated protein kinase (MAPK), a critical intermediate in the transduction of proliferative signals. Numerous observations have demonstrated that integrin-mediated cell anchorage can regulate the efficiency of signaling from RTKs to MAPK. Recently, a relationship between integrins and GPCR signaling has also emerged; however, little is understood concerning the mechanisms involved. Here, we investigate integrin regulation of GPCR signaling to MAPK, focusing on the P2Y class of GPCRs that function through activation of phospholipase Cbeta. P2Y receptor signaling to the downstream components mitogen-activated protein kinase kinase and MAPK is highly dependent on integrin-mediated cell anchorage. However, activation of upstream events, including inositol phosphate production and generation of calcium transients, is completely independent of cell anchorage. This indicates that integrins regulate the linkage between upstream and downstream events in this GPCR pathway, just as they do in some aspects of RTK signaling. However, the P2Y pathway does not involve cross-activation of a RTK, nor a role for Shc or c-Raf; thus, it is quite distinct from the classical RTK-Ras-Raf-MAPK cascade. Rather, integrin-modulated P2Y receptor stimulation of MAPK depends on calcium and on the activation of protein kinase C.
Insights
Integrins regulate G protein-coupled receptor (GPCR) signaling to mitogen-activated protein kinase (MAPK) by affecting downstream events, not upstream signaling. This integrin-GPCR-MAPK pathway is calcium-dependent and distinct from receptor tyrosine kinase pathways.
Area of Science:
- Cellular signaling pathways
- Integrin and GPCR biology
- Signal transduction mechanisms
Background:
- Receptor tyrosine kinases (RTKs) and G protein-coupled receptors (GPCRs) activate mitogen-activated protein kinase (MAPK), crucial for cell proliferation.
- Integrin-mediated cell anchorage influences RTK signaling to MAPK.
- The role of integrins in GPCR signaling, particularly to MAPK, is not well understood.
Purpose of the Study:
- To investigate how integrins regulate GPCR signaling to MAPK.
- To elucidate the mechanisms of integrin regulation in P2Y class GPCR signaling.
Main Methods:
- Investigated integrin regulation of P2Y GPCR signaling to MAPK.
- Assessed the dependence of upstream signaling events (inositol phosphate, calcium) and downstream events (MAPKK, MAPK) on cell anchorage.
- Examined the involvement of calcium, protein kinase C, RTKs, Shc, and c-Raf in the pathway.
Main Results:
- P2Y receptor signaling to MAPK is highly dependent on integrin-mediated cell anchorage.
- Upstream events like inositol phosphate production and calcium generation are independent of cell anchorage.
- Integrins modulate the linkage between upstream and downstream signaling in this GPCR pathway, distinct from RTK pathways.
Conclusions:
- Integrins regulate GPCR (P2Y) signaling to MAPK by affecting the connection between upstream and downstream events.
- This integrin-modulated pathway relies on calcium and protein kinase C activation.
- The mechanism is distinct from classical RTK-Ras-Raf-MAPK cascades, lacking RTK cross-activation and involvement of Shc or c-Raf.