Regulation of PTEN translation by PI3K signaling maintains pathway homeostasis.

The PI3K pathway regulates cell metabolism, proliferation, and migration, and its dysregulation is common in cancer. We now show that both physiologic and oncogenic activation of PI3K signaling increase the expression of its negative regulator PTEN. This limits the duration of the signal and output of the pathway. Physiologic and pharmacologic inhibition of the pathway reduces PTEN and contributes to the rebound in pathway activity in tumors treated with PI3K inhibitors and limits their efficacy. Regulation of PTEN is due to mTOR/4E-BP1-dependent control of its translation and is lost when 4E-BP1 is deleted. Translational regulation of PTEN is therefore a major homeostatic regulator of physiologic PI3K signaling and plays a role in reducing the pathway activation by oncogenic PIK3CA mutants and the antitumor activity of PI3K pathway inhibitors. However, pathway output is hyperactivated in tumor cells with coexistent PI3K mutation and loss of PTEN function.

A Loss of Epigenetic Control Can Promote Cell Death through Reversing the Balance of Pathways in a Signaling Network.

Epigenetic control of regulatory networks is only partially understood. Expression of Insulin-like growth factor-II (IGF2) is controlled by genomic imprinting, mediated by silencing of the maternal allele. Loss of imprinting of IGF2 (LOI) is linked to intestinal and colorectal cancers, causally in murine models and epidemiologically in humans. However, the molecular underpinnings of the LOI phenotype are not clear. Surprisingly, in LOI cells, we find a reversal of the relative activities of two canonical signaling pathways triggered by IGF2, causing further rebalancing between pro- and anti-apoptotic signaling. A predictive mathematical model shows that this network rebalancing quantitatively accounts for the effect of receptor tyrosine kinase inhibition in both WT and LOI cells. This mechanism also quantitatively explains both the stable LOI phenotype and the therapeutic window for selective killing of LOI cells, and thus prevention of epigenetically controlled cancers. These findings suggest a framework for understanding epigenetically modified cell signaling.

Signal amplification in growth cone gradient sensing by a double negative feedback loop among PTEN, PI(3,4,5)P3 and actomyosin.

Axon guidance during neural wiring involves a series of precisely controlled chemotactic events by the motile axonal tip, the growth cone. A fundamental question is how neuronal growth cones make directional decisions in response to extremely shallow gradients of guidance cues with exquisite sensitivity. Here we report that nerve growth cones possess a signal amplification mechanism during gradient sensing process. In neuronal growth cones of Xenopus spinal neurons, phosphatidylinositol-3,4,5-trisphosphate (PIP3), an important signaling molecule in chemotaxis, was actively recruited to the up-gradient side in response to an external gradient of brain-derived neurotrophic factor (BDNF), resulting in an intracellular gradient with approximate 30-fold amplification of the input. Furthermore, a reverse gradient of phosphatase and tensin homolog (PTEN) was induced by BDNF within the growth cone and the increased PTEN activity at the down-gradient side is required for the amplification of PIP3 signals. Mechanistically, the establishment of both positive PIP3 and reverse PTEN gradients depends on the filamentous actin network. Together with computational modeling, our results revealed a double negative feedback loop among PTEN, PIP3 and actomyosin for signal amplification, which is essential for gradient sensing of neuronal growth cones in response to diffusible cues.