Abstract
Cell migration and invasion play a key role in the breast cancer progression and are considered hallmarks of cancer. Migration requires the reorganization of the actin cytoskeleton, a process known to be regulated by Rho family GTPases via interaction with downstream effector proteins. p21-activated kinase (PAKs) are a family of six serine/threonine protein kinases, which are activated by the RhoGTPases Rac1 and/or Cdc42. PAKs have been implicated in many cellular process including cytoskeleton organization, cell motility, cell cycle progression, cell migration and cell survival. Overexpression of PAK isoforms has been found in different human cancer tissues including breast. Therefore, PAKs may provide a therapeutic target for the prevention breast cancer progression and metastasis. Whilst much is known about the biology of PAK1 less is known about the more recently described family member PAK6. Although, there is some evidence to suggest PAK6 is overexpressed in cancer cell lines relatively little is known about the role of PAK6 in cancer progression. This study detected endogenous PAK6 expression in multiple breast cancer cell lines. Moreover, in MDA-MB-231 cells expression of activated PAK6 induced cell rounding, whilst PAK6 deficient cells exhibit an elongated phenotype. Interestingly, this study has also found that treatment with Panobinostat reduces PAK6 expression and phenocopies the cell morphology observed for PAK6 knockdown cells. Furthermore, through immunoprecipitation and mass spectrometry analysis, interactions between PAK6 and unconventional RhoGTPases in breast cancer cells were identified in addition to interactions between PAK6 and regulators of cellular contractility. Taken together our results suggest that PAK6 can influence cell morphology via manipulation of RhoGTPase signalling.