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Cell Growth and Development

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

, , , &
Pages 5974-5985 | Received 19 Jan 2000, Accepted 17 May 2000, Published online: 28 Mar 2023
 

Abstract

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 Gα subunit pools (Gαi3 > Gαi2 >> Gα0), were both inhibited following βγ 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 βγ-pairings necessary for interaction with distinct kinase cascades.

ACKNOWLEDGMENTS

We express our gratitude to John Scott (Vollum Institute) and Peter Parker (ICRF) for helpful comments.

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