Rho-associated protein kinase

ROCK
Crystal structure of human ROCK I
Identifiers
Symbol	Rho-associated protein kinase
Alt. symbols	Rho-associated, coiled-coil-containing protein kinase
NCBI gene	579202
Other data
EC number	2.7.11.1

Rho-associated protein kinase (ROCK) is a kinase belonging to the AGC (PKA/ PKG/PKC) family of serine-threonine specific protein kinases. It is involved mainly in regulating the shape and movement of cells by acting on the cytoskeleton.

ROCKs (

Protein kinase C and Rho-associated protein kinase are involved in regulating calcium ion intake; these calcium ions, in turn stimulate a myosin light chain kinase, forcing a contraction.^[5] Rho-associated protein kinase are serine or threonine kinases that determine the calcium sensitivity in smooth muscle cells.

Function

ROCK plays a role in a wide range of different cellular phenomena, as ROCK is a downstream effector protein of the small GTPase Rho, which is one of the major regulators of the cytoskeleton.

1. ROCK is a key regulator of actin organization and thus a regulator of cell migration as follows:

Different substrates can be phosphorylated by ROCKs, including LIM kinase, myosin light chain (MLC) and MLC phosphatase. These substrates, once phosphorylated, regulate actin filament organization and contractility as follows:^[2]

• Amount of actin filaments

ROCK inhibits the depolymerization of actin filaments indirectly: ROCK phosphorylates and activates

ROCK also regulates cell migration by promoting cellular contraction and thus cell-substratum contacts. ROCK increases the activity of the motor protein myosin II by two different mechanisms:

• Firstly, phosphorylation of the myosin light chain (MLC) increases the myosin II ATPase activity. Thus several bundled and active myosins, which are asynchronously active on several actin filaments, move actin filaments against each other, resulting in the net shortenting of actin fibres.
• Secondly, ROCK inactivates MLC phosphatase, leading to increased levels of phosphorylated MLC.

Thus in both cases, ROCK activation by Rho induces the formation of actin stress fibers, actin filament bundles of opposing polarity, containing myosin II, tropomyosin, caldesmon and MLC-kinase, and consequently of focal contacts, which are immature integrin-based adhesion points with the extracellular substrate.^[2][7]

2. Other functions and targets

• RhoA-GTP stimulates the phospholipid phosphatase activity of
  tumor suppressor protein. This stimulation seems to depend on ROCK.^[8][9]
  In this way, PTEN is important to prevent uncontrolled cell division as is exhibited in cancer cells.
• ROCK plays an important role in cell cycle control, it seems to inhibit the premature separation of the two
  centrioles in G1, and is proposed to be required for contraction of the cleavage furrow, which is necessary for the completion of cytokinesis.^{[2][10][11][12][13][14]}
• ROCKs also seem to antagonize the insulin signaling pathway, resulting in a reduction of cell size and influence cell fate.^[2]
• ROCKS play a role in
  membrane blebbing, a morphological change seen in cells committed to apoptosis. The pro-apoptotic protease, caspase 3, activates ROCK kinase activity by cleaving the C-terminal PH domain. As a result, the autoinhibitory intramolecular fold of ROCK is abolished. ROCK also regulates MLC phosphorylation and actomyosin contractility, which regulate membrane blebbing.^[2]
• ROCKs contribute to neurite retraction by inducing growth cone collapse by activating actomyosin contractility. It is also possible that phosphorylation of collapsin response mediator protein-2 (CRMP2) by ROCK inhibits CRPM2 function of promoting axon outgrowth, resulting in growth cone collapse.^[2]
• ROCKs regulate cell-cell adhesion: Loss of ROCK activity seems to lead to loss of tight junction integrity in endothelial cells. In epithelial cells inhibition of ROCK seems to decrease tight junction integrity. Active ROCK in these cells seems to stimulate the disruption of E-Cadherin-mediated cell-cell contacts by activating actomyosin contractility.^[2]

3. Other ROCK targets

• NHE1 (a sodium hydrogen exchanger, involved in focal adhesions and actin organisation)
• intermediate filament proteins: Vimentin, GFAP (glial fibrillaric acidic protein), NF-L (neurofilament L protein)
• F-actin binding proteins: Adducin, EF-1&alpha (elongation factor, translation co-factor), MARCKS (myristylated alanine-rich C kinase substrate), Caponin (unknown function), and ERM (involved in linkage of the actin cytoskelton to the plasma membrane).

Homologues

The two mouse ROCK isoforms, ROCK1 and ROCK2, have high homology. They have 65% amino acid sequences in common and 92% homology within their kinase domains. ^{[1] [4]}

ROCKs are homologous to other metazoan kinases such as myotonic dystrophy kinase (

ROCK is a downstream effector molecule of the Rho GTPase Rho that increases ROCK kinase activity when bound to it.

Autoinhibition

ROCK activity is regulated by the disruption of an intramolecular autoinhibition. In general, the structure of ROCK proteins consists of an N-terminal kinase domain, a coiled-coiled region and a PH domain containing a cystein-rich domain (CRD) at the C-terminal. A Rho-binding domain (RBD) is located in close proximity just in front of the PH domain.

The kinase activity is inhibited by the

Disease

This section needs expansion. You can help by adding to it. (January 2020)

Research over the past two decades has shown that ROCK signaling plays an important role in many diseases including

Researchers are developing ROCK inhibitors such as RKI-1447 for treating various diseases including cancer.^[20][21] For example, such drugs have potential to prevent cancer from spreading by blocking cell migration, stopping cancer cells from spreading into neighboring tissue.^[1]

See also

• ROCK1

References