ROCK1

ROCK1 is also the name of the gene that encodes the protein ROCK1, a serine/threonine kinase. ROCK1 is activated when bound to the GTP-bound form of RhoA. The human ROCK1 gene is located on human chromosome 18 with specific location of 18q11.1. The location of the base pair starts at 18,529,703 and ends at 18,691,812 bp and translates into 1354 amino acids. ROCK1 has a ubiquitous tissue distribution, but subcellularly it is thought to colocalize with the centrosomes. This is consistent with its function as a key modulator of cell motility, tumor cell invasion, and actin cytoskeleton organization. == Structure and regulation ==

The ROCK1 structure is a serine/threonine kinase with molecular weight of 158 kDa. located at the amino or N-terminus of the protein, a coiled-coil region (residues 425-1100) This view of autoinhibition released by RhoA binding has been challenged by low resolution electron microscopy data showing ROCK to be a constitutive linear dimer 120 nm in length. According to this new data ROCK does not need to be activated by RhoA or phosphorylation because it is always active, and whether ROCK will phosphorylate its substrates (e.g. myosin regulatory light chain) depends only on their subcellular localization. Without RhoA binding, lipids such as arachidonic acid or sphingosine phosphorylcholine can increase ROCK1 activity 5- to 6-fold. These two lipids interact with the pleckstrin-homology domain, thus disrupting its ability to inhibit ROCK1. G-protein RhoE binds to the N-terminus of ROCK1 and inhibits its activity by preventing RhoA binding. Small G-proteins, Gem and Rad, have been shown to bind and inhibit ROCK1 function, but their mechanism of action is unclear. == Substrates and interactions ==

ROCK1 phosphorylation sites are at RXXS/T or RXS/T. ROCK1 activation by RhoA also promotes stabilization of F-actin, phosphorylation of regulatory myosin light chain (MLC) and an increase in contractility, which plays a crucial role in tumor cell migration and metastasis. This activated ROCK1 also activates LIM kinase, which, phosphorylates cofilin, inhibiting its actin-depolymerizing activity. This depolymerization results in stabilization of actin filaments and decreased branching which promotes contraction. Cardiac troponin is another ROCK1 substrate that upon phosphorylation causes reduction in tension in cardiac myocytes. ROCK1 also acts as a suppressor of inflammatory cell migration by regulating PTEN phosphorylation and stability. == Function ==

ROCK1 has a diverse range of functions in the body. It is a key regulator of actin-myosin contraction, stability, and cell polarity. These contribute to many progresses such as regulation of morphology, gene transcription, proliferation, differentiation, apoptosis and oncogenic transformation. Other functions involve smooth muscle contraction, actin cytoskeleton organization, stress fiber and focal adhesion formation, neurite retraction, cell adhesion and motility. These functions are activated by phosphorylation of DAPK3, GFAP, LIMK1, LIMK2, MYL9/MLC2, PFN1 and PPP1R12A. Additionally, ROCK1 phosphorylates FHOD1 and acts synergistically with it to promote SRC-dependent non-apoptotic plasma membrane blebbing. It is also required for centrosome positioning and centrosome-dependent exit from mitosis. == Interactions ==

ROCK1 has been shown to interact with: • LIMK1, and • RHOA. == Clinical significance ==

In humans, the main function of ROCK1 is actomyosin contractility. As mentioned before, this contributes to many proximal progresses such as regulation of morphology, motility, and cell–cell and cell–matrix adhesion. Angiogenesis Increased expression of RhoA and ROCK1 in endothelial cell migration pathways can cause an increase in angiogenesis and metastatic behavior in tumor cells. and pulmonary hypertension. == See also ==