SMURF and NEDD4: sharp shooters monitor the gate keepers and ion traffic controllers of lead astray cell.

It is becoming increasingly apparent that a complex bar code underlies the quantitative aspects of extracellular signal regulation. Cell type-specific and context-dependent transcriptional programs are triggered by sophisticated nanomachinery consisting of HECT enzymes which monitor signal generation, transduction and termination. How the HECT enzymes safeguard spatiotemporal organization was a fundamental question towards understanding the process of protein degradation and its functions in diverse biological processes. In this review we will dismantle how HECT E3 enzymes regulate the trafficking of many receptors, channels and transporters as well as how HECT enzymes negatively regulate each other. There is accumulating evidence that suggests an undeniable role of HECT enzymes in regulating mediators of the Wnt signal-transduction cascade. By contrast, little is known about the crosstalk of HECT enzymes with ATM and TRAIL in prostate cancer, but several hints have emerged. This review provides a broader snapshot for studying multiple pathways in parallel, rather than as separate entities.