Phosphorylation of P-Rex1 at serine 1169 participates in IGF-1R signaling in breast cancer cells.

Former reports demonstrated that P-Rex, a Rac guanine nucleotide exchange factor (GEF), participated in signaling upon activation of the ErbB receptor tyrosine kinases (RTKs). Activation of ErbB receptors turned on a phosphorylation/dephosphorylation cycle of P-Rex in which stimulation of serine(1169) phosphorylation played a critical role in the activation of this GEF. This precedent raised the important question of whether this P-Rex1 activation mechanism was restricted to ErbB receptors or could represent a general signaling event shared by several RTKs. To explore that possibility the effect of activation of distinct RTKs on the phosphorylation of P-Rex1 at serine(1169) was analyzed. Here we report that IGF-1 and FGF receptors activate serine(1169) phosphorylation of P-Rex1. P-Rex1 phosphorylation was required for IGF-1-induced up-regulation of Rac activity and cell proliferation. Moreover, IGF-1-induced adhesion was impaired in MCF7 breast cancer cells by knocking down P-Rex1. These results demonstrate that phosphorylation P-Rex1 at S(1169) represents a mechanism of activation of P-Rex1 common to multiple RTKs. We suggest that P-Rex proteins may act as novel and important transducers of pro-oncogenic signals that emanate from RTKs, and could even participate in other biological responses, such as metabolic control, which are not strictly related to the proliferation effects of RTKs.