Suppressive Effects of Tyrosine (Y129) Phosphorylation of Profilin I on Breast Cancer Progression

Abstract

It gets more and more intriguing to understand the role of multi-faceted Profilin, primarily an actin modulating protein, in breast cancer. Yet again, tyrosine 129 phosphorylation adds another interesting dimension to its role in breast cancer progression. Having discovered that Serine (S137) phosphorylation of profilin I imparts aggressive nature to breast cancer, we wanted to study the effect of Tyrosine (Y129) phosphorylation on the role of profilin I in breast cancer progression. These phosphorylations occur in the residues in the C-terminus of profilin that affect certain functions of profilin such as Polyproline-binding, PIP2 (Phosphatidylinositol 4,5-bisphosphate) and actin interactions. To examine this, we generated phosphorylation mutants PFN-Y129A and PFN-Y129A/S137A by site-directed mutagenesis. We had PFN-WT and PFN-S137A from previous studies. MDA-MB-231 cells and MCF7 cells demonstrated that single mutant PFN-Y129A and double mutant PFN-Y129A/S137A behaved differently than PFN-S137A. Surprisingly, Tyrosine phosphorylation prevents breast cancer progression. Transient transfection of these tyrosine phosphorylation mutants made cells more proliferative, migratory and gave anchorage-independence. They formed larger colonies than PFN-WT and more in number. An interesting fact observed was double phosphorylation mutant showed most aggression in breast cancer. Could this indicate a balance existing in these phosphorylations to prevent breast cancer progression and metastasis? We are yet to solve this dichotomous nature of Serine and Tyrosine phosphorylations and their impact in drug discovery.