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Receptor tyrosine kinase-GPCR signal complexes
N J Pyne1, C Waters, N A Moughal
1Department of Physiology and Pharmacology, Strathclyde Institute for Biomedical Sciences, University of Strathclyde, 27 Taylor St, Glasgow G4 0NR, Scotland, U.K. n.j.pyne@strath.ac.uk
Biochemical Society Transactions
|December 4, 2003
Summary
New receptor complexes form between growth factor and S1P/LPA receptors, enabling integrated signaling and enhanced activation of the p42/p44 MAPK pathway. This cross-talk influences cellular responses to growth factors and lysophospholipids.
Area of Science:
- Cellular signaling
- Molecular biology
- Receptor biology
Background:
- Growth factor receptors and G-protein-coupled receptors (GPCRs) mediate distinct cellular signals.
- Sphingosine 1-phosphate (S1P) and lysophosphatidic acid (LPA) are key lipid mediators acting through their cognate GPCRs.
- Cross-talk between these receptor families represents a novel signaling paradigm.
Purpose of the Study:
- To elucidate the molecular mechanisms of signal integration between receptor tyrosine kinases (RTKs) and S1P/LPA receptors.
- To investigate how these integrated signals modulate the p42/p44 mitogen-activated protein kinase (MAPK) pathway.
- To provide examples of cross-talk between specific RTKs (PDGFbeta, Trk A) and S1P/LPA receptors (S1P1, LPA1).
Main Methods:
- Investigating receptor complex formation at the plasma membrane and during endocytosis.
- Analyzing molecular events, including protein phosphorylation and receptor localization.
- Utilizing specific growth factors (PDGF, NGF) and receptor agonists (S1P, LPA) to probe signaling pathways.
Main Results:
- Formation of functional complexes between PDGFbeta receptor and S1P1 receptor, leading to PDGF-induced G(i)alpha phosphorylation and p42/p44 MAPK activation.
- Internalization of these complexes into endocytic vesicles containing MAPK pathway components.
- NGF-induced nuclear recruitment of the LPA1 receptor, potentially mediated by Trk A, suggesting novel nuclear signaling roles.
Conclusions:
- Receptor complexes between RTKs and S1P/LPA receptors create integrated signaling units.
- These complexes enhance p42/p44 MAPK pathway activation through proximity-dependent signaling and endocytic trafficking.
- Cross-talk extends to nuclear signaling, with implications for gene expression regulation by lipid mediators.