As recently reported by Li and collaborators [62], in human PC cell lines and in melanoma M2 cell line, the presence of the uncleaved GPI–PSS in pro-PrP allows the protein to bind the E3 ligase c-Cbl facilitating the IGF-1R ubiquitination for its degradation and consequent autophagic activation through Akt–ULK1 signaling axis, driving melanoma lung metastasis. The gene discussed is PRNP; the disease is melanoma.