title: MIG6 Is MEK Regulated and Affects EGF-Induced Migration in Mutant NRAS Melanoma.
abstract: Activating mutations in neuroblastoma RAS viral oncogene homolog (NRAS) are frequent driver events in cutaneous melanoma. NRAS is a guanosine triphosphate-binding protein whose most well-characterized downstream effector is RAF, leading to activation of mitogen-activated protein kinase (MEK)-extracellular signal-regulated protein kinase 1/2 signaling. Although there are no Food and Drug Administration-approved targeted therapies for melanoma patients with a primary mutation in NRAS, one form of targeted therapy that has been explored is MEK inhibition. In clinical trials, MEK inhibitors have shown disappointing efficacy in mutant NRAS patients, the reasons for which are unclear. To explore the effects of MEK inhibitors in mutant NRAS melanoma, we used a high-throughput reverse-phase protein array platform to identify signaling alterations. Reverse-phase protein array analysis of phospho-proteomic changes in mutant NRAS melanoma in response to trametinib indicated a compensatory increase in v-akt murine thymoma viral oncogene homolog signaling and decreased expression of mitogen-inducible gene 6 (MIG6), a negative regulator of epidermal growth factor receptor/v-erb-b2 erythroblastic leukemia viral oncogene homolog receptors. MIG6 expression did not alter the growth or survival properties of mutant NRAS melanoma cells. Rather, we identified a role for MIG6 as a negative regulator of epidermal growth factor-induced signaling and cell migration and invasion. In MEK-inhibited cells, further depletion of MIG6 increased migration and invasion, whereas MIG6 expression decreased these properties. Therefore, a decrease in MIG6 may promote the migration and invasiveness of MEK-inhibited mutant NRAS melanoma, especially in response to epidermal growth factor stimulation.
authors.affiliation: Department of Cancer Biology and Sidney Kimmel Cancer Center, Thomas Jefferson University Philadelphia, Pennsylvania, USA.
authors.forename: Ha Linh
authors.initials: HL
authors.lastname: Vu
authors.affiliation: Department of Cancer Biology and Sidney Kimmel Cancer Center, Thomas Jefferson University Philadelphia, Pennsylvania, USA.
authors.forename: Sheera
authors.initials: S
authors.lastname: Rosenbaum
authors.affiliation: Department of Cancer Biology and Sidney Kimmel Cancer Center, Thomas Jefferson University Philadelphia, Pennsylvania, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: Capparelli
authors.affiliation: Department of Cancer Biology and Sidney Kimmel Cancer Center, Thomas Jefferson University Philadelphia, Pennsylvania, USA.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Purwin
authors.affiliation: Department of Melanoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Davies
authors.affiliation: Department of Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
authors.forename: Adam C
authors.initials: AC
authors.lastname: Berger
authors.affiliation: Department of Cancer Biology and Sidney Kimmel Cancer Center, Thomas Jefferson University Philadelphia, Pennsylvania, USA; Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA. Electronic address: Andrew.Aplin@Jefferson.edu.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Aplin
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D017209:Apoptosis / Q000235:genetics; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics*; D015536:Down-Regulation; D004815:Epidermal Growth Factor / Q000378:metabolism*; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D008545:Melanoma / Q000235:genetics / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism*; D009154:Mutation; D012878:Skin Neoplasms / Q000235:genetics / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C484017:ERRFI1 protein, human; D008565:Membrane Proteins; D025521:Tumor Suppressor Proteins; D004815:Epidermal Growth Factor; D048369:MAP Kinase Kinase 1; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human