PKC[theta]-induced phosphorylations control the ability of Fra-1 to stimulate gene expression and cancer cell migration

The AP-1 transcription factor Fra-1 is aberrantly expressed in a large number of cancers and plays crucial roles in cancer development and progression by stimulating the expression of genes involved in these processes. However, the control of Fra-1 transactivation ability is still unclear and here we hypothesized that PKC[theta]-induced phosphorylation could be necessary to obtain a fully active Fra-1 protein. Using MCF7 stable cells overexpressing equivalent levels of unphosphorylated Fra-1 or PKC[theta]-phosphorylated Fra-1, we showed that PKC[theta]-induced phosphorylation of Fra-1 was crucial for the stimulation ofMMP1andIL6expression. Consistently, we found a significant positive correlation betweenPRKCQ(coding for PKC[theta]) andMMP1mRNA expression levels in human breast cancer samples. PKC[theta]-induced phosphorylations, in part at T217 and T227 residues, strongly and specifically increased Fra-1 transcriptional activity through the stimulation of Fra-1 transactivation domain, without affecting JUN factors. More importantly, these phosphorylations were required for Fra-1-induced migration of breast cancer cells and phosphorylated Fra-1 expression was enriched at the invasion front of human breast tumors. Taken together, our findings indicate that PKC[theta]-induced phosphorylation could be important for the function of Fra-1 in cancer progression.