The Role of the RhoA Activating Protein Net1 in Cancer Initiation and Progression

Rho GTPases are Ras-like proteins that contribute to many aspects of human cancer. However, unlike Ras, Rho proteins are not often mutagenically activated in cancers, but require activation by upstream proteins known as Rho GDP exchange factors (RhoGEFs). The neuroepithelial transforming gene 1 (Net1) is a RhoA/RhoB-specific GEF that is overexpressed in many cancers, and high levels of Net1 protein expression often correlate with reduced disease-free and overall survival. Net1 promotes multiple phenotypes in cancer cells, including cell motility, invasion, and proliferation. It does so by regulating diverse signaling pathways that ultimately control actin cytoskeletal organization, transcription, DNA damage signaling, and mitosis. In tumors, Net1 is required for tumor cell proliferation, tumor angiogenesis, and distant metastasis. In this review we will delineate the evidence supporting a role for Net1 in tumor progression, and describe mechanisms that regulate Net1 expression and cellular activity.