The formation of complexes between growth factor receptors and members of a family of G-protein-coupled receptors whose natural ligands are S1P (sphingosine 1-phosphate) and LPA (lysophosphatidic acid) represents a new signalling entity. This receptor complex allows for integrated signalling in response to growth factor and/or S1P/LPA and provides a mechanism for more efficient activation (due to integrated close-proximity signalling from both receptor classes) of the p42/p44 MAPK (mitogen-activated protein kinase) pathway. This article provides information on the molecular events at the interface between receptor tyrosine kinases and S1P/LPA receptors. Examples include the PDGF (platelet-derived growth factor)-induced tyrosine phosphorylation of Giα, released upon S1P1 receptor activation, which is required for initiation of the p42/p44 MAPK pathway. Critical to this event is the formation of endocytic vesicles containing functionally active PDGFβ receptor–S1P1 receptor complexes, which are internalized and relocated with components of the p42/p44 MAPK pathway. We also report examples of cross-talk signal integration between the Trk A (tropomyosin receptor kinase A) receptor and the LPA1 receptor in terms of the NGF (nerve growth factor)-dependent regulation of the p42/p44 MAPK pathway. NGF induces recruitment of the LPA1 receptor to the nucleus (delivery might be Trk A-dependent), whereupon the LPA1 receptor may govern gene expression via novel nuclear signalling processes.
- growth factor receptor
- lysophosphatidic acid
- p42/p44 mitogen-activated protein kinase
- sphingosine 1-phosphate (S1P)
679th Meeting of the Biochemical Society held at the University of Essex, Colchester, 2–4 July 2003
Abbreviations used: ASM, airway smooth muscle; GPCR, G-protein-coupled receptor; GRK2, G-protein-coupled receptor kinase 2; IGF-1, insulin-like growth factor-1; LPA, lysophosphatidic acid; MAPK, mitogen-activated protein kinase; NGF, nerve growth factor; PDGF, platelet-derived growth factor; PKC, protein kinase C; S1P, sphingosine 1-phosphate; SphK, sphingosine kinase; Trk, tropomyosin receptor kinase; MEK1, MAPK/extracellular-signal-regulated kinase kinase 1.
- © 2003 Biochemical Society