Ricerc@Sapienza

In mammals, Maml1 belongs to a family of proteins, which act as transcriptional coactivators for Notch signalling, an evolutionarily conserved pathway. Maml1 has been recently shown to act as a coactivator in other cell signalling pathways, including p53, MEF2C, ß-catenin, EGR1, NF-¿B, Runx2, Gli1 and YAP/TAZ in a Notch-independent manner. The E3 protein ubiquitin ligase (E3) Itch, belonging to the HECT family, binds different proteins diverting most of them to a proteasome/lysosome-dependent degradative pathway. In Hedgehog context, Itch activity is enhanced by the protein Numb, that binds the WW2 site of Itch, which is released from its self-inhibited conformation and induces Gli1 ubiquitination and proteasome degradation. Moreover, Numb interacts with Itch HECT domain to promote degradation of Notch intracellular domain. Preliminary data suggest a potential role of Maml1 in the post-transcriptional regulation of Gli1 and Notch1, preventing their degradation mediated by Itch. Besides a direct role as transcriptional coactivator, the observation suggests that Maml1 may play an important role in controlling the stability of the proteins through its C-terminal domain, still poorly characterized. So far, scientific research on Maml1 has been generally focused on its activity as a transcriptional coactivator, while overlooking its role in the post-transcriptional regulation. A thorough understanding of the molecular mechanism mediated by Maml1 to regulate Itch activity through Maml1 C-terminal domain, might lead to novel future therapeutic approaches directed against cancer. Maml1 and Itch are both key molecules that connect different signalling pathways. Therefore, the ability of Maml1 to regulate Itch activity could have an impact in controlling the force of several pathways, as Shh and Notch, in deregulated pathological contexts. This could set out new therapeutic approach based on the dual role of Maml1 and adding a piece in the understanding of tumour biology.