Abstract
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.
Highlights
Melanoma is one of the most common cancers and its global incidence has increased significantly during the last decades
Caveolin-1 (CAV1) is a scaffolding protein that plays a dual role in cancer
We used in vitro [2D and transendothelial cell migration (TEM), invasion] and in vivo assays, as well as genetic and biochemical approaches to address this question in B16F10 murine melanoma cells
Summary
Melanoma is one of the most common cancers and its global incidence has increased significantly during the last decades. Both have domains with unique functions that promote binding to specific collagens and proteoglycans, as well as to cell surfaces [5,6,7] The presence of such proteins enhances migration of B16 melanoma cells in Boyden chamber assays, where filters are precoated with either one of these glycoproteins as an attractant [8]. These experiments indicate that tumor cell migration is favored by haptotaxis towards immobilized attractant proteins, implicating non-collagenous, adhesive glycoproteins located in the interstitial space and on the basement membranes in directly promoting the invasion of some metastatic cell types in vivo. The best-characterized receptors for these ECM glycoproteins are the integrins
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