Biochemical Society Transactions

679th Meeting of the Biochemical Society

Receptor tyrosine kinase–GPCR signal complexes

N.J. Pyne, C. Waters, N.A. Moughal, B.S. Sambi, S. Pyne

Abstract

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.

  • differentiation
  • growth factor receptor
  • lysophosphatidic acid
  • p42/p44 mitogen-activated protein kinase
  • proliferation
  • sphingosine 1-phosphate (S1P)

Footnotes

  • 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.