The effect of RGS12 on PDGFbeta receptor signalling to p42/p44 mitogen activated protein kinase in mammalian cells

We have previously shown that the PDGFbeta receptor uses a classical GPCR-mediated pathway in order to induce efficient activation of p42/p44 MAPK in response to PDGF. We therefore, considered the possibility that GTPase accelerating proteins (RGS proteins), which regulate GPCR signalling, modulate...

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Bibliographic Details
Published in:Cellular signalling 2006-07, Vol.18 (7), p.971-981
Main Authors: Sambi, Balwinder S, Hains, Melinda D, Waters, Catherine M, Connell, Michelle C, Willard, Francis S, Kimple, Adam J, Pyne, Susan, Siderovski, David P, Pyne, Nigel J
Format: Article
Language:English
Subjects:
Animals
Cells, Cultured
Cytoplasmic Vesicles - metabolism
Enzyme Activation
Guinea Pigs
Humans
Mitogen-Activated Protein Kinase 1 - physiology
Mitogen-Activated Protein Kinase 3 - physiology
Mutation
Myocytes, Smooth Muscle - metabolism
Protein Structure, Tertiary
Protein Transport
Receptor, Platelet-Derived Growth Factor beta - genetics
Receptor, Platelet-Derived Growth Factor beta - physiology
RGS Proteins - genetics
RGS Proteins - physiology
Signal Transduction
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Summary:We have previously shown that the PDGFbeta receptor uses a classical GPCR-mediated pathway in order to induce efficient activation of p42/p44 MAPK in response to PDGF. We therefore, considered the possibility that GTPase accelerating proteins (RGS proteins), which regulate GPCR signalling, modulate PDGFbeta receptor-mediated signal transmission. Several lines of evidence were obtained to support functional interaction between the PDGFbeta receptor and RGS12 in HEK 293 and airway smooth muscle cells. Firstly, the over-expression of the RGS12 PDZ/PTB domain N-terminus or RGS12 PTB domain reduced the PDGF-induced activation of p42/p44 MAPK. Secondly, the RGS12 PDZ/PTB domain N-terminus and RGS12 PDZ domain can form a complex with the PDGFbeta receptor. Therefore, the results presented here provide the first evidence to support the concept that the PDZ/PTB domain N-terminus and/or the PTB domain of RGS12 may modulate PDGFbeta receptor signalling. In airway smooth muscle cells, over-expressed recombinant RGS12 and the isolated PDZ/PTB domain N-terminus co-localised with PDGFbeta receptor in cytoplasmic vesicles. To provide additional evidence for a role of the PDZ/PTB domain N-terminus, we used RGS14. RGS14 has the same C-terminal domain architecture of an RGS box, tandem Ras-binding domains (RBDs) and GoLoco motif as RGS12, but lacks the PDZ/PTB domain N-terminus. In this regard, RGS14 exhibited a different sub-cellular distribution compared with RGS12, being diffusely distributed in ASM cells. These findings suggest that RGS12 via its PDZ/PTB domain N-terminus may regulate trafficking of the PDGFbeta receptor in ASM cells.
ISSN:0898-6568