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Cell Growth and Development

Akt-Dependent and -Independent Survival Signaling Pathways Utilized by Insulin-Like Growth Factor I

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Pages 6711-6718 | Received 30 Mar 1998, Accepted 10 Aug 1998, Published online: 28 Mar 2023
 

ABSTRACT

Protein kinase B (PKB)/Akt is implicated in survival signaling in a wide variety of cells including fibroblasts and epithelial and neuronal cells. We and others have described a linear survival signaling cascade used by insulinlike growth factor I (IGF-I) that consists of the IGF-I receptor, phosphoinositide 3-kinase (PI3 kinase), Akt, and Bad. Activation of this pathway can be sufficient to protect cells from apoptosis. However, previous work had not determined whether this pathway is invariably necessary for protection from apoptosis or whether there are alternative survival signaling pathways. In this communication, we report the existence of two survival signaling pathways, one dependent on PI3 kinase and Akt and the other independent of these enzymes. We found that survival signaling initiated by IGF-I treatment of Rat-1 cells could be blocked by overexpression of a dominant negative kinase-deficient Akt (K179A) as well as by wortmannin. This demonstrates a survival signaling pathway dependent on PI3 kinase and Akt. However, when IGF-I receptors were overexpressed in a Rat-1 background (RIG cells), an alternative pathway became apparent, in which survival mediated by IGF-I was no longer sensitive to wortmannin or to overexpression of dominant negative Akt, even though Akt activation and Bad phosphorylation were still wortmannin sensitive. Experiments with inhibitors of RNA synthesis showed that transcriptional activation is dispensable for this alternative PI3 kinase/Akt-independent survival signaling. These findings demonstrate the existence of a new survival signaling pathway independent of PI3 kinase, Akt, and new transcription and which is evident in fibroblasts overexpressing the IGF-I receptor.

ACKNOWLEDGMENTS

We thank Kevin Overman for technical assistance, Anke Klippel for the Akt vectors, and Michael Greenberg and Robert Datta for vectors expressing Bad, antibodies, and valuable discussions. G.K. acknowledges Leonid Guzman, Inna Alesina, and Hans-Joerg Schaeffer, without whose help it would have been almost impossible to complete this work.

This work was supported by USPHS NIH grants CA 39076 and GM 47332.

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