title: Focal adhesion kinase promotes the aggressive melanoma phenotype.
abstract: Malignant melanoma continues to remain a significant health threat, with death often occurring as a result of metastasis. The metastatic phenotype typically is characterized by augmented tumor cell invasion and migration in addition to tumor cell plasticity as shown by vasculogenic mimicry. Therefore, understanding the molecular mechanisms that promote an aggressive phenotype is essential to predicting the likelihood of metastasis at a stage when intervention may be possible. This study focuses on the role of focal adhesion kinase (FAK), a cytoplasmic tyrosine kinase important for many cellular processes, including cell survival, invasion, and migration. We found FAK to be phosphorylated on its key tyrosine residues, Tyr397 and Tyr576, in only aggressive uveal and cutaneous melanoma cells, which correlates with their increased invasion, migration, and vasculogenic mimicry plasticity. Additionally, we confirmed the presence of FAK phosphorylated on Tyr397 and Tyr576 in both cutaneous and uveal melanoma tumors in situ. Examination of a functional role for FAK in aggressive melanoma revealed that disruption of FAK-mediated signal transduction pathways, through the expression of FAK-related nonkinase (FRNK), results in a decrease in melanoma cell invasion, migration, and inhibition of vasculogenic mimicry. Moreover, we found that FRNK expression resulted in a down-regulation of Erk1/2 phosphorylation resulting in a decrease in urokinase activity. Collectively, these data suggest a new mechanism involved in promoting the aggressive melanoma phenotype through FAK-mediated signal transduction pathways, thus providing new insights into possible therapeutic intervention strategies.
authors.affiliation: Children's Memorial Research Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60614-3394, USA.
authors.forename: Angela R
authors.initials: AR
authors.lastname: Hess
authors.forename: Lynne-Marie
authors.initials: LM
authors.lastname: Postovit
authors.forename: Naira V
authors.initials: NV
authors.lastname: Margaryan
authors.forename: Elisabeth A
authors.initials: EA
authors.lastname: Seftor
authors.forename: Galen B
authors.initials: GB
authors.lastname: Schneider
authors.forename: Richard E B
authors.initials: RE
authors.lastname: Seftor
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Nickoloff
authors.forename: Mary J C
authors.initials: MJ
authors.lastname: Hendrix
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D015536:Down-Regulation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism*; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D053504:Matrix Metalloproteinases, Membrane-Associated; D008545:Melanoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D008666:Metalloendopeptidases / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D012878:Skin Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D014162:Transfection; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism; D014604:Uveal Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology
chemical_list: C113183:FAK-related nonkinase; D011505:Protein-Tyrosine Kinases; D051416:Focal Adhesion Protein-Tyrosine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D014568:Urokinase-Type Plasminogen Activator; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2