A novel oncogenic protein in the Progranulin\EphA2 axis: the role of Myoferlin in bladder cancer

The growth factor progranulin plays a key role in bladder cancer by promoting cell motility and invasion. Until recently, the progranulin signaling receptor remained unknown precluding a full comprehension of progranulin action in cancer. Our laboratory has recently identified EphA2, a tyrosine kinase receptor, as the functional receptor for progranulin. Indeed, progranulin and not ephrin-A1, the canonical EphA2 ligand, is the predominant EphA2 ligand in bladder cancer. Progranulin promotes Akt-and Erk1/2-mediated EphA2 phosphorylation at Ser897, which might drive bladder tumorigenesis. Taking in account the role of progranulin\EphA2 axis in bladder cancer cell motility and invasion, our aim was to identify novel proteins in this pathway, which might contribute to downstream signaling cascades and modulate progranulin-evoked biological responses. Mass spectrometry analysis on T24 bladder cancer cells was performed to identify novel progranulin-mediated interactions with EphA2. Among the numerous EphA2 interacting proteins, Myoferlin was chosen for further studies because of its known oncogenic role. However, the relevance of this interaction and its role in the progranulin axis in bladder cancer is totally unexplored. The aim of this thesis is to characterize the role of myoferlin in bladder tumorigenesis, determine possible changes in the expression levels upon progranulin stimulation and define its action in the progranulin\EphA2 axis in bladder cancer.