Melusin is a muscle-specific protein involved in triggering compensatory cardiac hypertrophy in response to pressure overload. Despite the absence of a kinase domain, melusin is responsible for AKT and MAPKs activation in response to mechanical overload. To define the mechanism of action of melusin, we searched for molecular partners involved in the melusin-dependent signal transduction. We previously demonstrated that melusin is a component of the HSP90 chaperone machinery, directly interacts with HSP90, and possesses a chaperone activity per se. More recently we reported that melusin forms a supramolecular complex with c-Raf, MEK1/2 and ERK1/2 and that melusin-bound MAPKs are activated by pressure overload. We demonstrate that both FAK (Focal Adhesion Kinase) and IQGAP1, a scaffold protein for the ERK1/2 signalling cascade, are part of the melusin complex and are required for ERK1/2 activation in response to pressure overload. These findings point to melusin as a key role player in organizing a specific signalosome leading to ERK1/2 activation in cardiomyocytes in response to pressure overload. In parallel, we investigated the possible role of melusin in AKT signalling pathway. Here we demonstrate that melusin interacts with p85 PI3K regulatory subunit and that a phosphoinositide kinase activity co-precipitate together with melusin. Since PI3K is a well known upstream activator of AKT pathway we are currently investigating this interaction in greater details.