RhoGEFs as therapeutic targets

Abstract

RhoGEFs as Therapeutic Targets 1.1 Introduction. 1.1.1 The relevance Rho GTPase exchange factors as therapeutic targets. Rho GTPase signaling pathways are major regulators of eukaryotic cell dynamics, which control normal and pathological processes (Cook et al., 2014). They participate in cell migration, morphology, polarity and differentiation during embryonic development(Duquette and Lamarche-Vane, 2014; Fort and Théveneau, 2014). They are also involved in the pathological mechanisms of a variety of diseases, including hypertension(Shimokawa et al., 2016), cancer(Lin and Zheng, 2015), and neurodegenerative diseases(Stankiewicz and Linseman, 2014). Mammals have 20 Rho GTPases(Boureux et al., 2007) and 82 Rho GTPase exchange factors (RhoGEFs) that distribute between two families: the Dbl-related and the Dock-related RhoGEFs. The Dbl family counts 71 members (Jaiswal et al., 2013)(Cook et al., 2014) and there are 11 proteins in the Dock family(Gadea and Blangy, 2014). They activate RhoGTPase via their catalytic domain called the DH domain for the Dbl family or the DHR2 domain for the Dock family. The RhoGEFs are multidomain proteins: their catalytic domain is accompanied by various functional domains that can mediate the association of the GEF with membrane receptors or lipids for instance, or that provide the GEF with other enzymatic activities, such as kinase, phosphatase, or even GEF or GAP function towards other Ras-like GTPases. Rho GTPase signaling pathways can be targeted at various levels: the GTPases themselves but also GEFs, GAPs and downstream effectors.

Bone resorption by osteoclasts involves fine tuning of RHOA activity by its microtubule-associated exchange factor GEF-H1

“…Frontiers in Physiology frontiersin.org therapeutic targets in various pathologies (Blangy, 2017), including osteolytic diseases (Vives et al, 2015;Mounier et al, 2020). In fact, targeting GEFs makes it possible to target more specific signaling pathways than inhibiting the GTPases themselves, the latter being involved in many key cellular functions.…”

New Mechanisms Underlying Oncogenesis in Dbl Family Rho Guanine Nucleotide Exchange Factors

“…In humans, the largest family of RhoGEFs is the diffuse B-cell lymphoma (Dbl) family which is comprised of at least 69 members. Pathological changes in the activity of Dbl RhoGEFs are often due to overexpression or mutations that lead to loss of autoinhibition, contributing to diseases such as cancer, diabetes, and neuronal dysfunction (Barbosa et al, 2020;Blangy 2018;Lewis et al, 2010;Sosa et al, 2010). A second family, with 11 members, are the dedicators of cytokinesis (DOCK) proteins.…”