Cool-associated tyrosine phosphorylated protein-1 (Cat-1) is a signaling scaffold, as well as an ADP-ribosylation factor-GTPase-activating protein (ARF-GAP). Although best known for its role in cell migration, we recently showed that the ability of Cat-1 to bind paxillin, a major constituent of focal complexes, was also essential for the anchorage-independent growth of HeLa cervical carcinoma cells. Here, we set out to learn more about the underlying mechanism by which Cat-paxillin interactions mediate this effect. We show that knocking-down paxillin expression in HeLa cells promoted their ability to form colonies in soft-agar, whereas ectopically expressing paxillin in these cells inhibited this transformed growth phenotype. While knocking-down Cat-1 prevents HeLa cells from forming colonies in soft agar, when paxillin is knocked-down together with Cat-1, the cells are again able to undergo anchorage-independent growth. These results suggested that the requirement of Cat-1 for this hallmark of cellular transformation is coupled to its ability to bind paxillin and abrogate its actions as a negative regulator of anchorage-independent growth. We further show that knocking-down Cat-1 expression in HeLa cells leads to a reduction in Akt activation, which can be reversed by knocking-down paxillin. Moreover, expression of constitutively active forms of Akt1 and Akt2 restores the anchorage-independent growth capability of HeLa cells depleted of Cat-1 expression. Together, these findings highlight a novel mechanism, whereby interactions between Cat-1 and its binding partner paxillin are necessary to ensure sufficient Akt activation, such that cancer cells are able to grow under anchorage-independent conditions.
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