How the RhoA/ROCK Pathway Changes with Age and its Connection to the Diseases of Aging

Introduction

The Rho GTPases form a family of 20 closely related proteins with essential roles spanning diverse cellular processes. First known for their regulation of actin organization and dynamics, they are now also recognized as key mediators of gene expression and cell cycle progression¹.

Transforming protein RhoA, also known as Ras homolog family member A, was the first example to be discovered. Like other small GTPases, it serves as a “molecular switch” based on GTP/GDP binding status and is regulated by many other factors including guanine nucleotide exchange factors (GEFs), GTPase activating proteins (GAPs), and guanine nucleotide dissociation inhibitors (GDIs), through mechanisms that are reviewed in depth elsewhere².

RhoA signaling is propagated by an array of downstream effectors (Figure 1), the best characterized of which are the Rho-associated protein kinases, ROCK1 and ROCK2. In common with all Rho GTPases, RhoA contains a unique “insert domain” enabling direct interaction with these proteins³. When activated, ROCKs phosphorylate downstream targets including the PPP1R12A/MYPT1 subunit of myosin light chain phosphatase (MLCP), resulting in activation of MYL2/MLC2, the regulatory light chain of myosin II⁴. This effects actomyosin contractility, an underlying mechanism of force generation in cell motility and muscle contraction⁵. In addition, ROCKs can phosphorylate PPP1R14A/CPI-17, an inhibitor of MLCP⁶, and activate LIM domain kinases (LIMK1/2) toward cofilin phosphorylation to stabilize actin filaments⁷.

Ever since RhoA was proposed as an oncogene in the 1980s⁸ RhoA/ROCK signaling has been extensively studied in cancer and has been found to be dysregulated in many cancer types^9,10. However, this newsletter will focus on age-related changes that have also been identified across a range of studies, suggesting a role in other diseases of aging.