Understanding the interrelationship between material surface properties and the biological response to such materials remains a fundamental scientific challenge, as well as being of considerable practical importance in medicine. Through the use of a homologous series of copolymers of increasing hydrophobicity, we aimed to illuminate the interplay between material surface hydrophobicity and signalling events within cells in contact with this model system. Extending previous work, we hereby unravel key pathways controlling cell motility and the formation of a stellate phenotype, following interaction with polymer-coated surfaces. We reveal a comparative increase in cellular motility with increasing surface hydrophilicity, conjoint with an arrest in cell cycle progression. We also show an anomalous turnover of actin within the cell as a function of changing surface hydrophobicity. Finally, we show that cyclic adenosine monophosphate may be an effector of the cellular phenotype, as its production is increased in response to changes in the surface properties. These results highlight important signaling events which control actin rearrangements and the subsequent motility and its effectors.