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Molecular and Cellular Biology, August 2000, p. 5974-5985, Vol. 20, No. 16
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Receptor Isoforms Mediate Opposing Proliferative Effects through Gbeta gamma -Activated p38 or Akt Pathways

Lynda A. Sellers,* Forbes Alderton, Alan M. Carruthers, Marcus Schindler, and Patrick P. A. Humphrey

Glaxo Institute of Applied Pharmacology, Department of Pharmacology, University of Cambridge, Cambridge CB2 1QJ, United Kingdom

Received 19 January 2000/Returned for modification 15 March 2000/Accepted 17 May 2000

The opposing effects on proliferation mediated by G-protein-coupled receptor isoforms differing in their COOH termini could be correlated with the abilities of the receptors to differentially activate p38, implicated in apoptotic events, or phosphatidylinositol 3-kinase (PI 3-K), which provides a source of survival signals. These contrasting growth responses of the somatostatin sst2 receptor isoforms, which couple to identical Galpha subunit pools (Galpha i3 > Galpha i2 >> Galpha 0), were both inhibited following beta gamma sequestration. The sst2(a) receptor-mediated ATF-2 activation and inhibition of proliferation induced by basic fibroblast growth factor (bFGF) were dependent on prolonged phosphorylation of p38. In contrast, cell proliferation and the associated transient phosphorylation of Akt and p70rsk induced by sst2(b) receptors were blocked by the PI 3-K inhibitor LY 294002. Stimulation with bFGF alone had no effect on the activity of either p38 or Akt but markedly enhanced p38 phosphorylation mediated by sst2(a) receptors, suggesting that a complex interplay exists between the transduction cascades activated by these distinct receptor types. In addition, although all receptors mediated a sustained activation of extracellular signal-regulated kinases (ERK1 and ERK2), induction of the tumor suppressor p21cip1 was detected only following amplification of ERK and p38 phosphorylation by concomitant bFGF and sst2(a) receptor activation. Expression of constitutively active Akt in the presence of a p38 inhibitor enabled a proliferative response to be detected in sst2(a) receptor-expressing cells. These findings demonstrate that the duration of activation and a critical balance between the mitogen-activated protein kinase and PI 3-K pathways are important for controlling cell proliferation and that the COOH termini of the sst2 receptor isoforms may determine the selection of appropriate beta gamma -pairings necessary for interaction with distinct kinase cascades.

* Corresponding author. Mailing address: Glaxo Institute of Applied Pharmacology, Department of Pharmacology, University of Cambridge, Tennis Court Rd., Cambridge CB2 1QJ, United Kingdom. Phone: 44 1223 334 177. Fax: 44 1223 334 178. E-mail: wtem15797{at}glaxowellcome.co.uk.

Molecular and Cellular Biology, August 2000, p. 5974-5985, Vol. 20, No. 16
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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