P-Rex1 participates in Neuregulin-ErbB signal transduction and its expression correlates with patient outcome in breast cancer

Abstract

The Neuregulins and their receptors, the ErbB/HER subfamily of receptor tyrosine kinases, have critical roles in animal physiology, and their deregulation is frequent in cancer. Here we report the identification of the guanine nucleotide exchange factor, phosphatidylinositol 3,4,5-triphosphate-dependent Rac exchanger 1 (P-Rex1), as a novel mediator in signalling by ErbB/HER receptors. P-Rex1 was formerly described as a phosphoinositide 3-kinase and Gbc activated protein that regulates Rac function. We define how ErbB/HER receptors regulate P-Rex1 function, which involves dephosphorylation of inhibitory residues, and phosphorylation of activating residues of P-Rex. The net balance resulting from activation of this phosphorylation/dephosphorylation cycle of P-Rex1 favours Rac activation. Molecular and biological studies indicated that P-Rex1 phosphorylation regulated the proliferation of breast cancer cells, and P-Rex1 knockdown affected their migration or invasiveness, as well as their in vivo tumourigenic potential. Moreover, as we found correlation between high P-Rex1 expression and poor patient outcome in breast cancer, P-Rex1 targeting may be therapeutically relevant in cancer.

PREX1 Protein Function Is Negatively Regulated Downstream of Receptor Tyrosine Kinase Activation by p21-activated Kinases (PAKs)

“…PREX1 is phosphorylated downstream of neuregulin and IGF1 (18,19), and multiple studies have demonstrated that phosphorylation causes an electrophoretic mobility shift in PREX1 (18,30,31). In MCF7 breast cancer cells, we found that insulin also caused a PREX1 mobility shift (Fig.…”

“…Following the stimulation of certain RTKs, including the neuregulin-activated ErbB receptors, PREX1 regulates Rac activation, proliferation, adhesion, colony formation, and invasion of breast cancer cells (17)(18)(19). In breast cancer cell lines with HER2 amplification or PIK3CA-activating mutations, PREX1 is necessary for activation of ERK signaling through a Rac and PAK-dependent mechanism (20).…”

“…PREX1 is overexpressed in a variety of human cancers, including melanoma and breast, prostate, and colon cancer (17,(23)(24)(25)(26). PREX1 knockdown decreases tumor growth in xenograft mouse models of cancer using breast cancer cell lines (17,18). Additionally, PREX1 appears to have a specific role in metastasis.…”

“…Similarly, downstream of sphingosine 1-phosphate, PKA phosphorylates PREX1 to regulate an intramolecular interaction that reduces PREX1 GEF activity (49). Additionally, PREX1 is phosphorylated after the stimulation of RTKs with neuregulin, insulin-like growth factor 1 (IGF1), platelet-derived growth factor, and fibroblast growth factor, but the kinases that are responsible for these phosphorylation events are not known (18,19).…”

Identification of P-Rex1 as a Novel Rac1-Guanine Nucleotide Exchange Factor (GEF) That Promotes Actin Remodeling and GLUT4 Protein Trafficking in Adipocytes

“…Neutrophils lacking P-Rex1 exhibit decreased Rac2 activation in response to a chemoattractant formylmethionylleucylphenylalanine and attenuated formylmethionylleucylphenylalanine-induced F actin formation and superoxide production (32). In addition, P-Rex1 regulates neurite migration and differentiation (33)(34), and it is implicated as an oncogene in a range of malignancies (35)(36)(37). Interestingly, a detailed genotypic analysis has mapped PREX1 to a Type 2 diabetes susceptibility locus on chromosome 20q12-q13.1, suggesting its possible association with metabolic disorders; however, the role P-Rex1 plays in insulin signaling remains unexplored (38,39).…”