Rho-associated protein kinase (ROCK) signaling pathway (RhoA/ROCK pathway)

The Rho-associated protein kinase (ROCK) signaling pathway is a fundamental intracellular signaling cascade that regulates the actin cytoskeleton, influencing cell shape, motility, and contraction (UniProt P61586, Q13464, O75116). The pathway is triggered by the activation of Ras homolog family member A (RhoA), which in turn activates the downstream effectors ROCK1 and ROCK2. These serine/threonine kinases modulate the phosphorylation state of myosin light chain (MLC), either directly or by inhibiting myosin light chain phosphatase, thereby promoting actin-myosin cross-bridging and cellular tension (PMID: 26408238). Dysregulation of this pathway is a hallmark of various diseases, including glaucoma, where it increases resistance to aqueous humor outflow, and cardiovascular disorders, where it contributes to vasospasm and hypertension (PMID: 21248124). Pharmacological interventions targeting this pathway, such as the ROCK inhibitors fasudil and netarsudil, have demonstrated clinical utility in treating subarachnoid hemorrhage and ocular hypertension (PubChem CID 3344). However, the broad expression of these proteins across different tissues presents a challenge for systemic drug delivery, as global inhibition can lead to significant side effects like hypotension.

Other names

Rho-ROCK pathwayRho-kinase pathwayRhoA-ROCK1-ROCK2 axisRho-associated kinase signaling

ROCK inhibitors competitively bind to the ATP-binding site of ROCK1 and ROCK2, preventing the phosphorylation of downstream targets like myosin light chain (MLC) and myosin phosphatase target subunit 1 (MYPT1). This leads to decreased actin-myosin contractility and stabilization of the cytoskeleton.