| The role of tumor suppressor haploinsufficiency in oncogenesis is still poorly understood. The PTEN and TSC2 tumor suppressors function in the same pathway to antagonize mTOR activation by Akt, hence, compound heterozygous inactivation of Pten and Tsc2 in the mouse may in principle exacerbate the tumor phenotypes observed in the single mutants in a reciprocal manner. In contrast, we find that while Tsc2 heterozygosity enhances carcinogenesis in Pten+/- mice, tumorigenesis in Tsc2+/- mutants is surprisingly not accelerated by Pten heterozygosity, even though mTOR activation is cooperatively enhanced by compound Pten/Tsc2 heterozygosity. We show that the wild-type alleles of both Pten and Tsc2 are retained in prostate tumors from both Pten+/- and Pten +/-Tsc2+/- mice, whereas TSC-related tumor lesions are invariably associated with Tsc2 LOH in both Tsc2+/- and Pten +/-Tsc2+/- mice. These findings demonstrate that inactivation of TSC2 is epistatic to PTEN in the control of tumor initiation and progression and, importantly, that both Pten and Tsc2 are haploinsufficient for suppression of tumorigenesis initiated by Pten heterozygosity, while neither Pten nor Tsc2 is haploinsufficient for repression of carcinogenesis arising from Tsc2 heterozygosity, providing a rationale for the differential cancer susceptibility of the two human conditions associated with PTEN or TSC2 heterozygous mutations.; While mutation in the TSC2 gene has been known to be the initiating event of the tuberous sclerosis (TSC) tumor syndrome, it remains unclear whether and how posttranslational inactivation of TSC2 would play a role in TSC progression. We have recently identified a novel mechanism for tumorigenesis in TSC, in which Erk negatively regulates TSC2 by phosphorylating it at specific residues. This leads to its dissociation from TSC1 and activation of the mTOR pathway, thereby rendering TSC2 heterozygous cells tumorigenic. Importantly, we find that Erk-mediated TSC2 phosphorylation correlates with MAPK activation in TSC-associated brain lesions as well as in various cancers. These findings suggest that Erk may modulate mTOR signaling and contribute to disease progression through phosphorylation and inactivation of TSC2. |
