ROCK2

ROCK2 Full Name

Rho-associated, coiled-coil containing protein kinase 2

ROCK2 Introduction

ROCK2 encodes one of two mammalian isoforms of the Rho-associated coiled-coil containing protein kinase, a serine/threonine kinase that acts as a major downstream effector of the small GTPase RhoA. The protein is built from an N-terminal kinase domain, a long central coiled-coil tether of roughly 730 residues, and a C-terminal region containing a pleckstrin-homology and a C1 domain that mediate membrane association. Activated by RhoA, ROCK2 phosphorylates an array of cytoskeletal substrates including myosin light chain, the myosin-binding subunit of myosin phosphatase, LIM kinase, and adducin, thereby coordinating actomyosin contractility, stress-fiber formation, focal adhesion assembly, and cytokinesis. In its resting state ROCK2 is autoinhibited by an intramolecular interaction between its N-terminal extension and the kinase domain, and RhoA binding to the C-terminal domain relieves this clamp, allowing dimerization and access to substrates. Electron microscopy has revealed that full-length ROCK2 is a constitutive, roughly 120 nm extended dimer in which the coiled-coil functions as a molecular ruler that restricts kinase activity to a discrete zone of the actin cortex.

Figure 1. Structure of ROCK1 and ROCK2. (Source: Seccia TM, et al. 2020)

The physiological and pathological footprint of ROCK2 is broad. It is essential for smooth-muscle contraction, neurite retraction, cell migration, and the maintenance of vascular tone, and its deregulation has been linked to cancer progression, where overexpression correlates with poorer prognosis in breast cancer, and to inflammatory and autoimmune processes, where selective ROCK2 inhibition suppresses pathogenic IL-17 secretion. Pharmacologically, ROCK2 is the target of clinically advanced inhibitors such as KD025 (belumosudil) used in chronic graft-versus-host disease, validating the kinase as a tractable drug target. Mechanistic studies have further clarified that ROCK2 activation depends on an intramolecular hydrophobic-motif interaction with the N-terminal extension, enabling dimerization and substrate phosphorylation. Collectively, ROCK2 exemplifies how a single Rho effector translates spatial and signaling cues into precise control of cell shape, movement, and contractility. Because ROCK2 signaling intersects with fibrosis, vascular tone, and immune activation, selective inhibitors are being pursued not only for graft-versus-host disease but also for fibrotic and pulmonary indications, broadening the clinical relevance of this Rho effector.

Alternate Names for ROCK2

ROCK2; Rho-associated, coiled-coil containing protein kinase 2; ROCK-II; rho-associated protein kinase 2; p164 ROCK-2; rho-associated, coiled-coil-containing protein kinase II;

• 1. Seccia TM, et al. ROCK (RhoA/Rho Kinase) in Cardiovascular-Renal Pathophysiology: A Review of New Advancements. J Clin Med. 2020 May 2;9(5):1328.
  2. Truebestein L, et al. A molecular ruler regulates cytoskeletal remodelling by the Rho kinases. Nat Commun. 2015 Dec 1;6:10029.