Activated Rac1, but not the tumorigenic variant Rac1b, is ubiquitinated on Lys 147 through a JNK‐regulated process

Abstract

In all eukaryotic cells, Rho GTPases (Rho, Rac, Cdc42) control basic cellular functions, including actin cytoskeleton organization, vesicular trafficking, transcriptional regulation and cell cycle progression, and are therefore major intracellular regulators of cell growth and division, and cell migration [1,2]. Consistent with their key role in cell signaling, dysregulation of Rho-dependent pathways is being found to be causally involved in the pathophysiology of a growing number of human diseases [3]. Hence, mutations in genes encoding Rho regulators are responsible for human developmental defects and, particularly, several

Rho GTPases: Regulation and roles in cancer cell biology

“…For example, Rac1 is ubiquitinated only when in the active form and bound to the plasma membrane. 31,34 By contrast, RhoA can be ubiquitinated in different conformations by different mechanisms. Nucleotide-free RhoA and GDP-RhoA are substrates of Smurf1 ubiquitin ligase 35 while only GDPRhoA is a substrate of the BACURD-cullin3 complex.…”

The Rac1 hypervariable region in targeting and signaling

“…137 This post-translational modification is distinct from Rac1 ubiquitylation, which occurs on Lys147 and triggers its degradation. 88 Preventing Rac1 sumoylation did not alter its localization to membranes, nor the binding to GEFs and effector proteins, but did reduce GTP binding. Rac1 binding to GTP, as well as its partitioning in "liquid-ordered plasma membrane domains," is also stimulated by palmitoylation of Cys178, which is immediately N-terminal of the HVR.…”

“…Because of this latter finding, regulation of Rac1 ubiquitylation was investigated. Rac1 is known to be ubiquitylated at Lys147 88 and this occurs primarily on activated Rac1. 89,90 Analysis of Rac1 ubiquitylation showed that loss of Caveolin1 promotes mono-ubiquitylation of Rac1.…”

Rho GTPases, oxidation, and cell redox control

“…[29][30][31] Rac1 is the only Rho family GTPase shown to be monoubiquitinated, and this modification affects Rac1 localization. 32 Ubiquitin is a highly regulated and reversible modification that can be removed by deubiquitinating enzymes (DUBs); however, Ras-and Rho-specific DUBs have yet to be discovered.…”