Nevertheless, the widespread coupling of PI3K–Akt and Hippo pathway signalling in many tissues is potentially of major significance for human cancer because activation of PI3K–Akt signalling (in PIK3CA or PTEN mutant cells) causes formation of highly proliferative malignant tumours, while mutation of TSC1 or TSC2 leads to formation of relatively benign tumours [75, 81]. This evidence concerns the gene TSC2 and cancer.