Figure 1 - Sites of action of PI-103 in the PI3 kinase signaling pathway.


From the following article

Drugging the PI3 kinome

Paul Workman, Paul A Clarke, Sandrine Guillard & Florence I Raynaud

Nature Biotechnology 24, 794 - 796 (2006)

doi:10.1038/nbt0706-794

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Class I PI3 kinase isoforms (e.g., p110alpha) are activated downstream of ligand-bound receptor tyrosine kinases (e.g., insulin and IGF-1 receptors) through interactions involving Ras and p85 regulatory subunits that are often promoted by adaptor proteins such as IRS-1. Activated PI3 kinase catalyzes the production of the second messenger PIP3, which recruits the PKB/Akt protein kinase to the membrane where it is activated through dual phosphorylation (denoted by 'P') by PDK1 and the mTOR-rictor complex (mTORC2)10. Active PKB/Akt phosphorylates multiple substrates resulting in the regulation of several cellular processes, many of which are often deregulated in cancer. Negative regulation of the PI3 kinase pathway is mediated by the PTEN phosphatase (depleting PIP3 levels) and reduced expression of IRS-1 mediated by p70S6K. PI-103 (inset) inhibits p110alpha and both mTORC2 and the mTOR-raptor complex (mTORC1). This inhibits the PI3 kinase pathway at multiple sites and potentially accounts for the anticancer effects of PI-103 in malignant glioma4.

Bob Crimi

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