title: GAB2 induces tumor angiogenesis in NRAS-driven melanoma.
abstract: GAB2 is a scaffold protein with diverse upstream and downstream effectors. MAPK and PI3K signaling pathways are known effectors of GAB2. It is amplified and overexpressed in a variety of human tumors including melanoma. Here we show a previously undescribed role for GAB2 in NRAS-driven melanoma. Specifically, we found that GAB2 is co-expressed with mutant NRAS in melanoma cell lines and tumor samples and its expression correlated with metastatic potential. Co-expression of GAB2(WT) and NRAS(G12D) in melanocytes and in melanoma cells increased anchorage-independent growth by providing GAB2-expressing cells a survival advantage through upregulation of BCL-2 family of anti-apoptotic factors. Of note, collaboration of GAB2 with mutant NRAS enhanced tumorigenesis in vivo and led to an increased vessel density with strong CD34 and VEGFR2 activity. We found that GAB2 facilitiated an angiogenic switch by upregulating HIF-1α and VEGF levels. This angiogenic response was significantly suppressed with the MEK inhibitor PD325901. These data suggest that GAB2-mediated signaling cascades collaborate with NRAS-driven downstream activation for conferring an aggressive phenotype in melanoma. Second, we show that GAB2/NRAS signaling axis is non-linear and non-redundant in melanocytes and melanoma, and thus are acting independent of each other. Finally, we establish a link between GAB2 and angiogenesis in melanoma for the first time. In conclusion, our findings provide evidence that GAB2 is a novel regulator of tumor angiogenesis in NRAS-driven melanoma through regulation of HIF-1α and VEGF expressions mediated by RAS-RAF-MEK-ERK signaling.
authors.affiliation: Department of Dermatology, Columbia University, New York, NY 10032, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Yang
authors.forename: J
authors.initials: J
authors.lastname: Wu
authors.forename: A
authors.initials: A
authors.lastname: Demir
authors.forename: M
authors.initials: M
authors.lastname: Castillo-Martin
authors.forename: R D
authors.initials: RD
authors.lastname: Melamed
authors.forename: G
authors.initials: G
authors.lastname: Zhang
authors.forename: M
authors.initials: M
authors.lastname: Fukunaga-Kanabis
authors.forename: R
authors.initials: R
authors.lastname: Perez-Lorenzo
authors.forename: B
authors.initials: B
authors.lastname: Zheng
authors.forename: D N
authors.initials: DN
authors.lastname: Silvers
authors.forename: G
authors.initials: G
authors.lastname: Brunner
authors.forename: S
authors.initials: S
authors.lastname: Wang
authors.forename: R
authors.initials: R
authors.lastname: Rabadan
authors.forename: C
authors.initials: C
authors.lastname: Cordon-Cardo
authors.forename: J T
authors.initials: JT
authors.lastname: Celebi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007231:Infant, Newborn; D008545:Melanoma / Q000098:blood supply* / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic; D009857:Oncogenes / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D051381:Rats; D014158:Transcription, Genetic; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C490895:GAB2 protein, human; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008565:Membrane Proteins; D042461:Vascular Endothelial Growth Factor A; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human