TY - JOUR TI - E3 ubiquitin ligase PARK2, an inhibitor of melanoma cell growth, is repressed by the oncogenic ERK1/2-ELK1 transcriptional axis AU - Montagnani, Valentina AU - Maresca, Luisa AU - Apollo, Alessandro AU - Pepe, Sara AU - Carr, Ryan M. AU - Fernandez-Zapico, Martin E. AU - Stecca, Barbara T2 - Journal of Biological Chemistry AB - Malignant melanoma, the most aggressive form of skin cancer, is characterized by high prevalence of BRAF/NRAS mutations and hyperactivation of extracellular signal-regulated kinase 1 and 2 (ERK1/2), mitogen-activated protein kinases (MAPK), leading to uncontrolled melanoma growth. Efficacy of current targeted therapies against mutant BRAF or MEK1/2 have been hindered by existence of innate or development of acquired resistance. Therefore, a better understanding of the mechanisms controlled by MAPK pathway driving melanogenesis will help develop new treatment approaches targeting this oncogenic cascade. Here, we identify E3 ubiquitin ligase PARK2 as a direct target of ELK1, a known transcriptional effector of MAPK signaling in melanoma cells. We show that pharmacological inhibition of BRAF-V600E or ERK1/2 in melanoma cells increases PARK2 expression. PARK2 overexpression reduces melanoma cell growth in vitro and in vivo and induces apoptosis. Conversely, its genetic silencing increases melanoma cell proliferation and reduces cell death. Further, we demonstrate that ELK1 is required by the BRAF-ERK1/2 pathway to repress PARK2 expression and promoter activity in melanoma cells. Clinically, PARK2 is highly expressed in wild type BRAF and NRAS melanomas, but it is expressed at low levels in melanomas carrying BRAF/NRAS mutations. Overall, our data provide new insights into the tumor suppressive role of PARK2 in malignant melanoma and uncover a novel mechanism for the negative regulation of PARK2 via the ERK1/2-ELK1 axis. These findings suggest that reactivation of PARK2 may be a promising therapeutic approach to counteract melanoma growth. DA - 2020/09/16/ PY - 2020 DO - 10.1074/jbc.RA120.014615 DP - www.jbc.org SP - jbc.RA120.014615 J2 - J. Biol. Chem. LA - en SN - 0021-9258, 1083-351X UR - http://www.jbc.org/content/early/2020/09/16/jbc.RA120.014615 Y2 - 2020/09/17/21:51:45 KW - extracellular-signal-regulated kinase (ERK) KW - melanoma KW - parkin KW - transcription factor KW - tumor suppressor gene ER -