Extracellular matrix-specific Caveolin-1 phosphorylation on tyrosine 14 is linked to augmented melanoma metastasis but not tumorigenesis
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Rina Ortiz1,2,3,7, Jorge Díaz1,2,4, Natalia Díaz1,2,7, Lorena Lobos-Gonzalez1,5,6, Areli Cárdenas1,2,7, Pamela Contreras1,2, María Inés Díaz1,2, Ellen Otte8, Justin Cooper-White8, Vicente Torres1,4, Lisette Leyton1,2,7, Andrew F.G. Quest1,2
1Center for Molecular Studies of the Cell (CEMC), Advanced Center for Chronic Diseases (ACCDiS), Faculty of Medicine, Universidad de Chile, Santiago, Chile
2Laboratory of Cellular Communication, Program of Cell and Molecular Biology, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, Universidad de Chile, Santiago, Chile
3Universidad Bernardo O Higgins, Facultad de Salud, Departamento de Ciencias Químicas y Biológicas, Santiago, Chile
4Institute for Research in Dental Sciences, Faculty of Dentistry, Universidad de Chile, Santiago, Chile
5Andes Biotechnologies SA, Ñuñoa, Santiago, Chile
6Fundación Ciencia & Vida, Ñuñoa, Santiago, Chile
7Biomedical Neuroscience Institute (BNI) Santiago, Chile
8Australian Institute for Bioengineering & Nanotechnology, The University of Queensland, St. Lucia, Queensland, Australia
Andrew F.G. Quest, email: email@example.com
Lisette Leyton, email: firstname.lastname@example.org
Keywords: Caveolin-1, cancer, dual role, migration, invasion
Received: December 04, 2015 Accepted: May 16, 2016 Published: May 31, 2016
Caveolin-1 (CAV1) is a scaffolding protein that plays a dual role in cancer. In advanced stages of this disease, CAV1 expression in tumor cells is associated with enhanced metastatic potential, while, at earlier stages, CAV1 functions as a tumor suppressor. We recently implicated CAV1 phosphorylation on tyrosine 14 (Y14) in CAV1-enhanced cell migration. However, the contribution of this modification to the dual role of CAV1 in cancer remained unexplored. Here, we used in vitro [2D and transendothelial cell migration (TEM), invasion] and in vivo (metastasis) assays, as well as genetic and biochemical approaches to address this question in B16F10 murine melanoma cells. CAV1 promoted directional migration on fibronectin or laminin, two abundant lung extracellular matrix (ECM) components, which correlated with enhanced Y14 phosphorylation during spreading. Moreover, CAV1-driven migration, invasion, TEM and metastasis were ablated by expression of the phosphorylation null CAV1(Y14F), but not the phosphorylation mimicking CAV1(Y14E) mutation. Finally, CAV1-enhanced focal adhesion dynamics and surface expression of beta1 integrin were required for CAV1-driven TEM. Importantly, CAV1 function as a tumor suppressor in tumor formation assays was not altered by the Y14F mutation. In conclusion, our results provide critical insight to the mechanisms of CAV1 action during cancer development. Specific ECM-integrin interactions and Y14 phosphorylation are required for CAV1-enhanced melanoma cell migration, invasion and metastasis to the lung. Because Y14F mutation diminishes metastasis without inhibiting the tumor suppressor function of CAV1, Y14 phosphorylation emerges as an attractive therapeutic target to prevent metastasis without altering beneficial traits of CAV1.
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