Hamartomas are benign lesions that develop in a range of dominantly inherited tumour syndromes, including tuberous sclerosis complex (TSC) and Peutz–Jeghers syndrome (PJS). Two groups now have evidence for a molecular link between TSC and PJS.

Although developing in different tissues, the hamartomas seen in patients with either TSC or PJS have a similar histology. One of the known phosphorylation targets of the PJS tumour-suppressor kinase LKB1 is the energy-sensing AMP kinase (AMPK), which is activated by high AMP (low ATP) levels. TSC2 — a tumour suppressor involved in TSC and a regulator of target of rapamycin (TOR) kinase — is a direct target of AMPK, prompting Corradetti et al. and Shaw et al. to look closely at the molecular pathways disrupted through the loss of Lkb1.

Both groups initially verified that LKB1 can negatively regulate phosphorylation of the TOR kinase substrates S6 kinase and 4EBP1. Phosphorylation of both of these proteins was increased in cells with non-functional LKB1. Both groups then examined the regulation of this pathway by manipulating the activity of AMPK. Shaw and co-workers used an AMP mimetic to stimulate AMPK and showed that TSC2 was phosphorylated only in the presence of functional LKB1. Corradetti and colleagues used an AMPK inhibitor to show that LKB1 was unable to alter the phosphorylation status of S6 kinase in the absence of functional AMPK.

What is the physiological relevance of these findings? TOR is a component of the energy-sensing pathway and Tsc2−/− cells undergo apoptosis when deprived of glucose, a response that is blocked by the TOR inhibitor rapamycin. Both groups demonstrate the same sensitivity and response to rapamycin in Lkb1−/− cells in the absence of glucose. Corradetti and colleagues showed that, like Tsc2−/− cells, Lkb1−/− cells secrete increased levels of vascular endothelial growth factor, which is attenuated in the presence of rapamycin. Shaw and colleagues have also found that Lkb1+/− mice develop intestinal hamartomas that mimic those arising in patients with PJS and these also have increased levels of TOR activity.

Therefore, the similarities between PJS and TSC are because of LKB1 and TSC2 belonging to the same kinase signalling pathway. Their affect on TOR also indicates that rapamycin and its analogues could be used to treat hamartomas in these patients. However, despite these similarities, intriguing questions remain. Why, for example, do patients with PJS develop hamartomas in the intestine, whereas patients with TSC have widespread tissue involvement? One explanation might be that loss of TSC2 function affects more than energy signalling pathways; Tsc2−/− cells also fail to respond to growth-factor-mediated pathways that remain intact in Lkb1−/− cells.