Cellular and Molecular Roles of the Akt Protein Kinase in Breast Carcinomas

摘要

Akt is a serine/threonine kinase that has been implicated in the initiation and/or progression of breast cancers. In order to gain an understanding of how Akt promotes malignant transformation, we identified proteins that are regulated by Akt, including the Bm-1 transcription factor, the B-Raf serine/threonine kinase, and the Elk-1 transcription factor, Bm1 co- associates with Akt1 in vivo and is phosphorylated in vitro by Akt1. The site of phosphorylation of Brni by Akt1 was mapped to S407. This site is conserved in POU domain family members, suggesting a general role for Akt in their biology. Akt also negatively regulates the enzymatic activity of B-Raf in vitro and in vivo by phosphorylating two residues in the amino-terminal regulatory domain of B-Raf. Akt also negatively regulates the activity and level of the Elk-1 transcription factor. Thus, Akt may promote transformation and cell survival in part by altering gene expression through regulation of transcription factors and in part by regulating the Ras/Raf pathway by phosphorylating and downregulating the activity of the B-Raf kinase.