The P-Rexl/Rac signaling pathway as a point of convergence for HER/ErbB receptor and GPCR responses

摘要

Guanine nucleotide Exchange Factors (GEFs) are responsible for mediating GDP/GTP exchange for specific small G proteins, such as Rac. There has been substantial evidence for the involvement of Rac-GEFs in the control of cancer cell migration and metastatic progression. We have previously established that the Rac-GEF P-Rex1 is a mediator of actin cytoskeleton rearrangements and cell motility in breast cancer cells downstream of HER/ErbB receptors and the G-Protein Coupled Receptor (GPCR) CXCR4. P-Rex1is highly expressed in luminal A and B breast cancer compared to normal mammary tissue, whereas expression is very low in basal breast cancer, and its expression correlates with the appearance of metastasis in patients. Here, we discuss the involvementof P-Rex1 as an effector of oncogenic/metastatic receptors in breast cancer and underscore its relevance in the convergence of receptor-triggered motile signals. In addition, we provide an overview of our recent findings describing a cross-talk between HER/ErbB receptors and CXCR4, and how this impacts on the activation of P-Rex1/Rac1 signaling, as well as highlight challenges that lie ahead. We propose a model in which P-Rexl acts as a crucial node for the integration of upstream inputs from HER/ErbB receptors and CXCR4 in luminal breast cancer cells.