Focal adhesion kinase promotes the aggressive melanoma phenotype

Angela R Hess; Lynne-Marie Postovit; Naira V Margaryan; Elisabeth A Seftor; Galen B Schneider; Richard E B Seftor; Brian J Nickoloff; Mary J C Hendrix

doi:10.1158/0008-5472.CAN-05-2172

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Focal adhesion kinase promotes the aggressive melanoma phenotype

Journal article

Open access

Peer reviewed

Focal adhesion kinase promotes the aggressive melanoma phenotype

Angela R Hess, Lynne-Marie Postovit, Naira V Margaryan, Elisabeth A Seftor, Galen B Schneider, Richard E B Seftor, Brian J Nickoloff and Mary J C Hendrix

Cancer research (Chicago, Ill.), Vol.65(21), pp.9851-9860

11/01/2005

DOI: 10.1158/0008-5472.CAN-05-2172

PMID: 16267008

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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.

Phosphorylation

Protein-Tyrosine Kinases - metabolism

Humans

Melanoma - enzymology

Metalloendopeptidases - metabolism

Extracellular Signal-Regulated MAP Kinases - metabolism

Uveal Neoplasms - enzymology

Cell Movement - physiology

Neoplasm Metastasis

Protein-Tyrosine Kinases - genetics

Matrix Metalloproteinases, Membrane-Associated

Skin Neoplasms - enzymology

Transfection

Melanoma - genetics

Skin Neoplasms - pathology

Uveal Neoplasms - genetics

Uveal Neoplasms - pathology

Focal Adhesion Protein-Tyrosine Kinases - metabolism

Matrix Metalloproteinase 2 - metabolism

Neoplasm Invasiveness

Down-Regulation

Melanoma - pathology

Urokinase-Type Plasminogen Activator - metabolism

Skin Neoplasms - genetics

Cell Line, Tumor

Details

Title: Subtitle: Focal adhesion kinase promotes the aggressive melanoma phenotype
Creators: Angela R Hess - Children's Memorial Research Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60614-3394, USA
Lynne-Marie Postovit
Naira V Margaryan
Elisabeth A Seftor
Galen B Schneider
Richard E B Seftor
Brian J Nickoloff
Mary J C Hendrix
Resource Type: Journal article
Publication Details: Cancer research (Chicago, Ill.), Vol.65(21), pp.9851-9860
Publisher: United States
DOI: 10.1158/0008-5472.CAN-05-2172
PMID: 16267008
ISSN: 0008-5472
eISSN: 1538-7445
Grant note: CA88046-02S / NCI NIH HHS CA59702 / NCI NIH HHS P0-1-CA27502 / NCI NIH HHS CA80318 / NCI NIH HHS
Language: English
Date published: 11/01/2005
Academic Unit: Dentistry Administration; Prosthodontics
Record Identifier: 9984066082602771

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