The Rac GTPase in Cancer: From Old Concepts to New Paradigms

Abstract

Rho family GTPases are critical regulators of cellular functions that play important roles in cancer progression. Aberrant activity of Rho small G-proteins, particularly Rac1 and their regulators, is a hallmark of cancer and contributes to the tumorigenic and metastatic phenotypes of cancer cells. This review examines the multiple mechanisms leading to Rac1 hyperactivation, particularly focusing on emerging paradigms that involve gain-of-function mutations in Rac and guanine nucleotide exchange factors, defects in Rac1 degradation, and mislocalization of Rac signaling components. The unexpected pro-oncogenic functions of Rac GTPase-activating proteins also challenged the dogma that these negative Rac regulators solely act as tumor suppressors. The potential contribution of Rac hyperactivation to resistance to anticancer agents, including targeted therapies, as well as to the suppression of antitumor immune response, highlights the critical need to develop therapeutic strategies to target the Rac pathway in a clinical setting. Cancer Res; 77(20); 5445-51. ©2017 AACR.

Figure 1. Mechanisms of Rac deregulation in cancer

Activating mutations in Rac1 have been recently found in various cancers, including Rac1^P29S, identified as a driver mutation in melanomas. Another hyperactive form is the splice variant Rac1b present in a number of cancers. Degradation of Rac1 by the proteasome contributes to the control of Rac protein expression levels, and it could be impaired in tumors as a consequence of missense mutations in the ubiquitin ligase HACE1. Hyperactivation of Rac-GEFs as a consequence of overexpression or mutation is also a prominent cause of Rac1 deregulation in cancer. Rac-GAPs have a complex role in cancer, as their reduced expression contributes to Rac1 hyperactivation in some tumors, however overexpression of specific GAPs has been also linked to aggressiveness, most likely through GAP-independent functions. Abnormal nuclear Rac1 localization is also common in cancer, an effect that has been associated with improper nucleocytoplasmic shuttling. Deregulated GEF activity in nuclear compartments, such as the nucleolus, may lead to localized Rac1 activation and enhanced ribosomal RNA (rRNA) synthesis.