Extracellular matrix-specific Caveolin-1 phosphorylation on tyrosine 14 is linked to augmented melanoma metastasis but not tumorigenesis.
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.
Center for Molecular Studies of the Cell (CEMC), Advanced Center for Chronic Diseases (ACCDiS), Faculty of Medicine, Universidad de Chile, Santiago, Chile.|Laboratory of Cellular Communication, Program of Cell and Molecular Biology, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, Universidad de Chile, Santiago, Chile.|Universidad Bernardo O Higgins, Facultad de Salud, Departamento de Ciencias Químicas y Biológicas, Santiago, Chile.|Biomedical Neuroscience Institute (BNI) Santiago, Chile.
Rina
R
Ortiz
Center for Molecular Studies of the Cell (CEMC), Advanced Center for Chronic Diseases (ACCDiS), Faculty of Medicine, Universidad de Chile, Santiago, Chile.|Laboratory of Cellular Communication, Program of Cell and Molecular Biology, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, Universidad de Chile, Santiago, Chile.|Institute for Research in Dental Sciences, Faculty of Dentistry, Universidad de Chile, Santiago, Chile.
Jorge
J
Díaz
Center for Molecular Studies of the Cell (CEMC), Advanced Center for Chronic Diseases (ACCDiS), Faculty of Medicine, Universidad de Chile, Santiago, Chile.|Laboratory of Cellular Communication, Program of Cell and Molecular Biology, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, Universidad de Chile, Santiago, Chile.|Biomedical Neuroscience Institute (BNI) Santiago, Chile.
Natalia
N
Díaz
Center for Molecular Studies of the Cell (CEMC), Advanced Center for Chronic Diseases (ACCDiS), Faculty of Medicine, Universidad de Chile, Santiago, Chile.|Andes Biotechnologies SA, Ñuñoa, Santiago, Chile.|Fundación Ciencia & Vida, Ñuñoa, Santiago, Chile.
Lorena
L
Lobos-Gonzalez
Center for Molecular Studies of the Cell (CEMC), Advanced Center for Chronic Diseases (ACCDiS), Faculty of Medicine, Universidad de Chile, Santiago, Chile.|Laboratory of Cellular Communication, Program of Cell and Molecular Biology, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, Universidad de Chile, Santiago, Chile.|Biomedical Neuroscience Institute (BNI) Santiago, Chile.
Areli
A
Cárdenas
Center for Molecular Studies of the Cell (CEMC), Advanced Center for Chronic Diseases (ACCDiS), Faculty of Medicine, Universidad de Chile, Santiago, Chile.|Laboratory of Cellular Communication, Program of Cell and Molecular Biology, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, Universidad de Chile, Santiago, Chile.
Pamela
P
Contreras
Center for Molecular Studies of the Cell (CEMC), Advanced Center for Chronic Diseases (ACCDiS), Faculty of Medicine, Universidad de Chile, Santiago, Chile.|Laboratory of Cellular Communication, Program of Cell and Molecular Biology, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, Universidad de Chile, Santiago, Chile.
María Inés
MI
Díaz
Australian Institute for Bioengineering & Nanotechnology, The University of Queensland, St. Lucia, Queensland, Australia.
Ellen
E
Otte
Australian Institute for Bioengineering & Nanotechnology, The University of Queensland, St. Lucia, Queensland, Australia.
Justin
J
Cooper-White
Center for Molecular Studies of the Cell (CEMC), Advanced Center for Chronic Diseases (ACCDiS), Faculty of Medicine, Universidad de Chile, Santiago, Chile.|Institute for Research in Dental Sciences, Faculty of Dentistry, Universidad de Chile, Santiago, Chile.
Vicente
V
Torres
Center for Molecular Studies of the Cell (CEMC), Advanced Center for Chronic Diseases (ACCDiS), Faculty of Medicine, Universidad de Chile, Santiago, Chile.|Laboratory of Cellular Communication, Program of Cell and Molecular Biology, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, Universidad de Chile, Santiago, Chile.|Biomedical Neuroscience Institute (BNI) Santiago, Chile.
Lisette
L
Leyton
Center for Molecular Studies of the Cell (CEMC), Advanced Center for Chronic Diseases (ACCDiS), Faculty of Medicine, Universidad de Chile, Santiago, Chile.|Laboratory of Cellular Communication, Program of Cell and Molecular Biology, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, Universidad de Chile, Santiago, Chile.
Andrew F G
AF
Quest
D000818:Animals; D063646:Carcinogenesis; D051242:Caveolin 1 / Q000737:chemistry / Q000378:metabolism*; D002448:Cell Adhesion; D002465:Cell Movement; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005353:Fibronectins / Q000737:chemistry; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D007797:Laminin / Q000737:chemistry; D008175:Lung Neoplasms / Q000556:secondary; D008297:Male; D008545:Melanoma / Q000378:metabolism*; D008546:Melanoma, Experimental; D051379:Mice; D008810:Mice, Inbred C57BL; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010766:Phosphorylation; D012878:Skin Neoplasms / Q000378:metabolism*; D014443:Tyrosine / Q000737:chemistry*
C495540:CAV1 protein, human; C495541:Cav1 protein, mouse; D051242:Caveolin 1; D005353:Fibronectins; D019012:Integrin beta1; D007797:Laminin; D014443:Tyrosine
Caveolin-1; cancer; dual role; invasion; migration