The role of G-protein coupled receptors and associated proteins in receptor tyrosine kinase signal transduction
Introduction
A signalling pathway that is typically activated by G-protein coupled receptor (GPCR) agonists, such as lysophosphatidic acid (LPA) and by growth factor receptor agonists, such as epidermal growth factor (EGF) and platelet-derived growth factor (PDGF), is the p42/p44 mitogen-activated protein kinase (p42/p44 MAPK) cascade. Classical activation of p42/p44 MAPK in response to either EGF or PDGF involves the growth factor binding to its specific cell surface receptor, which dimerises, becomes auto-tyrosine phosphorylated and subsequently recruits various intracellular adaptor molecules to it that transduce the growth factor signal to the low molecular weight G-protein, Ras, which then activates the p42/p44 MAPK cascade. Initially it seemed that GPCRs and receptor tyrosine kinases (RTK), along with their respective down-stream effectors, represented distinct and linear signalling units that converged on down-stream targets, such as p42/p44 MAPK. It has since become abundantly clear that this is not the case and that multiple levels of cross talk exist between both receptor systems.
Section snippets
GPCR-mediated transactivation of RTKs
Transactivation of receptor tyrosine kinases is typified by a GPCR-dependent increase in the tyrosine phosphorylation of the growth factor receptor, which leads to the recruitment of scaffold proteins, via their SH2 domain interaction with tyrosine phosphate residues. This leads to down-stream signalling from the receptor tyrosine kinase. GPCR agonists such as LPA [1], angiotensin, endothelin [2] and bradykinin [3] can transactivate receptor tyrosine kinases, such as the EGF receptor, by
Receptor tyrosine kinase and G-protein coupled receptor signal integration
The constitutive shedding of HB-EGF in the presence of GPCR agonists does not account for the co-mitogenic effect of exogenous added GPCR agonists with growth factors, particularly as this can occur using maximal concentrations of each. However, GPCR/receptor tyrosine kinase signal integration, where there is also an obligate requirement to integrate receptor tyrosine kinase activity in order to facilitate GPCR-mediated signal transmission can explain the concept of co-mitogenicity. The feature
Phosphorylation of GPCR by Akt
Lee et al. have demonstrated that S1P-induced endothelial cell migration requires the Akt-mediated phosphorylation of the GPCR, S1P1 [99]. Activated Akt binds to the S1P1 receptor and phosphorylates the third intracellular loop at the T(236) residue. Transactivation of S1P1 by Akt is not required for G(i)-dependent signalling but is indispensable for Rac activation, cortical actin assembly and chemotaxis. Indeed, a T236A S1P1 receptor mutant sequestered Akt and acted as a dominant-negative GPCR
Conclusion
It is abundantly clear from this review that there is a large body of evidence, which demonstrates that receptor tyrosine kinases can use proximal located G-protein/GPCR signalling components in an integrated manner to induce activation of key regulatory pathways linked to cellular processes, such as cell proliferation and differentiation. Receptor tyrosine kinases (e.g. receptors for PDGF, insulin, EGF) appear to form associated complexes with GPCRs, which, in certain cases, can supply
Acknowledgements
Research in the authors’ laboratory is funded by the BBSRC and Wellcome Trust.
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