Figure 8.
A model for TSC1-2 regulation of insulin signaling to PI3K. The elevated production of the inositol phospholipid PIP3 by PI3K and its antagonism by PTEN (and 5-phosphatases; not depicted) determines the activation of downstream responses such as activation of PKB. A further downstream response to PKB activation may be the inactivation of TSC1-2 via phosphorylation of tuberin, resulting in S6K activation. In our model, TSC1-2 promotes insulin-like growth factor signaling to PI3K by repressing a negative feedback loop from mTOR/S6K to the adaptor molecule IRS-1. This negative regulation by TSC1-2 may be on mTOR effectors (Jaeschke et al., 2002) or on mTOR directly (Tee et al., 2002). A similar negative feedback involving S6K repression of PKB activation has also been described in Drosophila (Radimerski et al., 2002), although the target of dS6K's inhibitory action here is not known. Repression of IRS-1 by mTOR/S6K occurs via both a transcriptional repression of IRS-1 gene expression mediated by both S6K1 and S6K2 and by direct phosphorylation of IRS-1 protein close to the PTB domain by S6K1. Therefore, failure to activate PI3K may restrict the malignant potential of TSC-defective cells.