Receptor tyrosine kinase-GPCR signal complexes.
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 G(i)alpha, released upon S1P(1) 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 PDGFbeta receptor-S1P(1) 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 LPA(1) receptor in terms of the NGF (nerve growth factor)-dependent regulation of the p42/p44 MAPK pathway. NGF induces recruitment of the LPA(1) receptor to the nucleus (delivery might be Trk A-dependent), whereupon the LPA(1) receptor may govern gene expression via novel nuclear signalling processes.
Pyne
N J
NJ
Department 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
Waters
C
C
Moughal
N A
NA
Sambi
B S
BS
Pyne
S
S
D002460:Cell Line; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D020932:Nerve Growth Factor / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D049312:Receptors, Lysophospholipid; D015398:Signal Transduction
D020574:Proto-Oncogene Proteins c-sis; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D049312:Receptors, Lysophospholipid; D020932:Nerve Growth Factor; D020794:Receptor Protein-Tyrosine Kinases; D019204:GTP-Binding Proteins