Involvement of Ankrd2 in the progression of osteosarcoma and rhabdomyosarcoma
Ankrd2 is a protein belonging to the family of MARPs (Muscle Ankyrin Repeat Proteins) and, like the other members, such as Ankrd1 e Ankrd23, features four ankyrin repeats and one sequence of nuclear localization. In particular, Ankrd2 is mainly expressed in fibers of skeletal muscle, albeit it has been identified also in heart. In muscle fibers, Ankrd2 interacts with sarcomeric structural proteins, as well as with proteins involved in intracellular signaling or in the transcription of DNA. Based on this evidence, we think that Ankrd2 might act as a mediator of the cellular response to mechanical stress inducing the activation of specific signaling cascades. In this scenario, Ankrd2 is thus considered an effector of mechanosignaling and mechanotransduction (Cenni V. et al, 2019).
Our evidence demonstrate that in muscle cells, upon oxidative stress signals, Ankrd2 modulates muscle differentiation (Cenni V. et al, 2011), as well as the inflammatory response dependent of Nf-kB (Bean C. et al, 2014). These studies also prove that these functions are modulated by Ankrd2 phosphorylation at serine 99. Through a phospho-proteomic approach, we have proved that this residue is phosphorylated by the protein kinase Akt2. These data for the first time have related Ankrd2 to proteins of intracellular signaling (Cenni V. et al, 2011). In muscle cells, serine 99 phosphorylation promotes the nuclear translocation of Ankrd2 (Cenni V. et al, 2011). In parallel studies have demonstrated that an altered localization of Ankrd2, induced by pathological mutant forms of lamin A/C increases the cellular susceptibility to oxidative stress, suggesting a role for Ankrd2 in the pathogenesis of muscular laminopathies (Angori S. et al, 2017).
Ankrd2 expression has been reported also in cells derived from tumors and in tumor tissues, including colon carcinoma, ovaric carcinoma, renal oncocytoma and rhabdomyosarcoma. However, despite this, no study has never described or hypothesized any involvement for Ankrd2 in cancer progression. Our preliminary studies demonstrate that Ankrd2 is expressed in cellular lines derived from human osteosarcoma and rhabdomyosarcoma and that the modulation of Ankrd2 expression is able to affect cellular proliferation.
It is therefore our aim to evaluate if Ankrd2 has a role in the progression of these pathologies. Osteosarcomas and rhabdomyosarcomas are malignancies particularly insidious, because of an high tendency to form metastases.
What we plan to do is therefore to:
- determine if serine 99 phosphorylation is involved in proliferation of cancer cells;
- determine if Ankrd2 and its phopshorylation at serine 99 are involved in tumor cells’ migration and invasion;
3. identify an intracellular signal cascade in which Ankrd2 takes part of, and hence identify regulators and/or effectors of Ankrd2.