Receptor tyrosine kinase-G-protein coupled receptor complex signaling in mammalian cells

N.J. Pyne, C. Waters, J.S.L. Long, N. Akhtar Moughal, G. Tigyi, S. Pyne

Research output: Contribution to journalLiterature reviewpeer-review

21 Citations (Scopus)


Recent evidence suggests that signals transmitted by receptor tyrosine kinases (RTK) and G-protein coupled receptors (GPCR) are integrated to promote efficient growth factor stimulation of cellular responses (Waters et al., 2004). The important feature of this model is that agents that disrupt GPCR function (e.g. pertussis toxin (PTX) and the C-terminal tail of GRK2, which sequesters Gbg subunits) block the growth factor-stimulated activation of various effector modules, such as p42/p44 mitogen activated protein kinase (p42/p44 MAPK) (Luttrell et al., 1995; Fedorov et al., 1998; Conway et al., 1999; Alderton et al., 2001; Waters et al., 2003). This invokes a role for GPCR and places the G-protein down-stream from the RTK. There is now a body of evidence which supports this type of model in mammalian cells. For instance, the IGF-1 and FGF receptors use the G-protein, Gi to stimulate activation of p42/p44 MAPK in fibroblasts and skeletal muscle, respectively (Luttrell et al., 1995; Fedorov et al., 1998). We have also reported that the platelet derived growth factor (PDGF)-induced activation of c-Src and p42/p44 MAPK can be reduced by PTX and CT-GRK2 in airway smooth muscle (ASM) cells and HEK 293 cells (Conway et al., 1999; Alderton et al., 2001; Waters et al., 2003) and that the overexpression
of Gia2 enhances the stimulation of p42/p44 MAPK by PDGF, associated with
a PDGFb receptor kinase-catalyzed tyrosine phosphorylation of Gia2 (Alderton et al., 2001). The tyrosine phosphorylation of endogenous Gia2 might prevent reformation of the inactive Gabg complex, thereby prolonging the lifetime of active G-protein subunits, including Gbg. The integrative signal mechanism is distinct from the transactivation of RTK by GPCR agonists, which involves stimulation of the tyrosine phosphorylation of the RTK.
Original languageEnglish
Pages (from-to)271-280
Number of pages10
JournalAdvances in Enzyme Regulation
Issue number1
Publication statusPublished - 2007


  • receptor tyrosine kinases
  • G-protein coupled receptors


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