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ROCK1
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<h2 id="gene-and-expression">Gene and expression</h2> <p>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 <a href="/facts/Chromosome_18/2xgSEp6a">chromosome 18</a> with specific location of 18q11.1.<a class="footnote-ref" id="fnref:3" href="#fn:3"><sup>3</sup></a> The location of the base pair starts at 18,529,703 and ends at 18,691,812 <a href="/facts/Base_pair/xmPpPQ9W">bp</a> and <a href="/facts/Translation_(biology)/JcPC1rth">translates</a> into 1354 <a href="/facts/Amino_acids/WDxYwBny">amino acids</a>.<a class="footnote-ref" id="fnref:4" href="#fn:4"><sup>4</sup></a> </p><p>ROCK1 has a ubiquitous tissue distribution, but <a href="/facts/Subcellular_localization/50QUENGB">subcellularly</a> it is thought to colocalize with the <a href="/facts/Centrosomes/QlTtIIeI">centrosomes</a>. This is consistent with its function as a key modulator of <a href="/facts/Cell_migration/5ySAMquQ">cell motility</a>, <a href="/facts/Metastasis/4dadbm6z">tumor cell invasion</a>, and <a href="/facts/Actin/Hu3qIUL9">actin</a> cytoskeleton organization.<a class="footnote-ref" id="fnref:5" href="#fn:5"><sup>5</sup></a> In rats, ROCK1 is expressed in the lung, liver, spleen, kidney, and testis.<a class="footnote-ref" id="fnref:6" href="#fn:6"><sup>6</sup></a><a class="footnote-ref" id="fnref:7" href="#fn:7"><sup>7</sup></a><a class="footnote-ref" id="fnref:8" href="#fn:8"><sup>8</sup></a> </p> <h2 id="structure-and-regulation">Structure and regulation</h2> <p>The ROCK1 structure is a serine/threonine kinase with molecular weight of 158 kDa.<a class="footnote-ref" id="fnref:9" href="#fn:9"><sup>9</sup></a> It is a homodimer composed of a catalytic kinase domain (residues76-338)<a class="footnote-ref" id="fnref:10" href="#fn:10"><sup>10</sup></a> located at the amino or <a href="/facts/N-terminus/yKYpuaBJ">N-terminus</a> of the protein, a <a href="/facts/Coiled-coil/U0YEzcB4">coiled-coil</a> region (residues 425-1100)<a class="footnote-ref" id="fnref:11" href="#fn:11"><sup>11</sup></a> containing the <a href="/facts/Rho_factor/uLmcoQgN">Rho-binding domain</a>, and a pleckstrin-homology domain (residues 1118-1317)<a class="footnote-ref" id="fnref:12" href="#fn:12"><sup>12</sup></a> with a <a href="/facts/GC-content/nRoVl7gw">cysteine-rich</a> domain. When a substrate is absent, ROCK1 is an autoinhibited loop structure. Enzyme activity of ROCK1 is inhibited when the <a href="/facts/Pleckstrin_homology_domain/0lqnQpg5">pleckstrin-homology</a> and Rho-binding domains in the <a href="/facts/C-terminus/ws4scHgT">C-terminus</a> independently bind to the N-terminus kinase domain. When a substrate such as GTP-bound RhoA binds to the Rho-binding region of the coiled-coil domain, the interactions between the N-terminus and the C-terminus are disrupted, thus activating the protein. Cleavage of the C-terminal inhibitory domain by <a href="/facts/Caspase-3/FpjEwtwR">caspase-3</a> during <a href="/facts/Apoptosis/8dVzSm4y">apoptosis</a> can also activate the kinase.<a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a> </p><p>This view of autoinhibition released by RhoA binding has been challenged by low resolution electron microscopy data showing ROCK to be a constitutive linear <a href="/facts/Protein_dimer/c8LwFJPG">dimer</a> 120 nm in length.<a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a> According to this new data ROCK does not need to be activated by RhoA or <a href="/facts/Phosphorylation/LXUEEeIL">phosphorylation</a> because it is always active, and whether ROCK will phosphorylate its substrates (e.g. <a href="/facts/Myosin_light_chain/b3jgBuIe">myosin regulatory light chain</a>) depends only on their subcellular localization.<a class="footnote-ref" id="fnref:15" href="#fn:15"><sup>15</sup></a> </p><p>There is one other isoform of ROCK known as ROCK2. ROCK2 is located at 2p24 and is highly homologous with ROCK1 with an overall amino acid sequence identity of 65%.<a class="footnote-ref" id="fnref:16" href="#fn:16"><sup>16</sup></a> The identity in the Rho-binding domain is 58%<a class="footnote-ref" id="fnref:17" href="#fn:17"><sup>17</sup></a> and approximately 92%<a class="footnote-ref" id="fnref:18" href="#fn:18"><sup>18</sup></a> in the kinase domain. The ROCK isoforms are encoded by two different identified genes and are ubiquitously expressed.<a class="footnote-ref" id="fnref:19" href="#fn:19"><sup>19</sup></a> </p><p>GTPase-RhoA binding can increase the activity of ROCK1 by 1.5-2-fold.<a class="footnote-ref" id="fnref:20" href="#fn:20"><sup>20</sup></a> Without RhoA binding, lipids such as <a href="/facts/Arachidonic_acid/7fMTra6z">arachidonic acid</a> or <a href="/facts/Sphingomyelin/KruAelVs">sphingosine phosphorylcholine</a> can increase ROCK1 activity 5- to 6-fold.<a class="footnote-ref" id="fnref:21" href="#fn:21"><sup>21</sup></a><a class="footnote-ref" id="fnref:22" href="#fn:22"><sup>22</sup></a> These two lipids interact with the pleckstrin-homology domain, thus disrupting its ability to inhibit ROCK1.<a class="footnote-ref" id="fnref:23" href="#fn:23"><sup>23</sup></a> <a href="/facts/G_protein/HKkcfgGP">G-protein</a> <a href="/facts/Rnd3/u3wYIFfs">RhoE</a> binds to the N-terminus of ROCK1 and inhibits its activity by preventing RhoA binding. Small G-proteins, <a href="/facts/GEM_(gene)/8pbP38rg">Gem</a> and <a href="/facts/RRAD_(gene)/41sbJ9Rk">Rad</a>, have been shown to bind and inhibit ROCK1 function, but their mechanism of action is unclear.<a class="footnote-ref" id="fnref:24" href="#fn:24"><sup>24</sup></a> </p> <h2 id="substrates-and-interactions">Substrates and interactions</h2> <p>ROCK1 phosphorylation sites are at RXXS/T or RXS/T.<a class="footnote-ref" id="fnref:25" href="#fn:25"><sup>25</sup></a> More than 15 ROCK1 substrates have been identified and activation from these substrates most often leads to actin filament formation and cytoskeleton rearrangements.<a class="footnote-ref" id="fnref:26" href="#fn:26"><sup>26</sup></a> <a href="/facts/PPP1R12A/vu7gToHE">MYPT-1</a> is involved in a pathway for <a href="/facts/Smooth_muscle_tissue/mpcpTsHp">smooth muscle</a> contraction. When ROCK1 is activated by binding of GTPase RhoA it produces multiple signaling cascades. For example, RhoA is one of the downstream signaling cascades activated by vascular endothelial growth factor (<a href="/facts/VEGF/kNDc0Xj0">VEGF</a>). ROCK1 acts as a negative regulator of VEGF <a href="/facts/Endothelial_cell/L4ENFVnw">endothelial cell</a> activation and angiogenesis.<a class="footnote-ref" id="fnref:27" href="#fn:27"><sup>27</sup></a> ROCK1 activation by RhoA also promotes stabilization of <a href="/facts/F-actin/Hu3qIUL9">F-actin</a>, phosphorylation of regulatory <a href="/facts/Myosin_light_chain/b3jgBuIe">myosin light chain</a> (MLC) and an increase in contractility, which plays a crucial role in tumor cell migration and metastasis.<a class="footnote-ref" id="fnref:28" href="#fn:28"><sup>28</sup></a> This activated ROCK1 also activates <a href="/facts/LIM_kinase/6esH801p">LIM kinase</a>, which, phosphorylates <a href="/facts/Cofilin/wYS09rVM">cofilin</a>, inhibiting its <a href="/facts/Actin_depolymerizing_factor/MBfeNSwD">actin-depolymerizing</a> activity.<a class="footnote-ref" id="fnref:29" href="#fn:29"><sup>29</sup></a> This depolymerization results in stabilization of actin filaments and decreased branching which promotes contraction. </p><p>Cardiac <a href="/facts/Troponin/gQdzvCCb">troponin</a> is another ROCK1 substrate that upon phosphorylation causes reduction in tension in cardiac <a href="/facts/Myocytes/cP7Jea3q">myocytes</a>.<a class="footnote-ref" id="fnref:30" href="#fn:30"><sup>30</sup></a> ROCK1 also acts as a suppressor of inflammatory cell migration by regulating <a href="/facts/PTEN_(gene)/Xg6MAcHm">PTEN</a> phosphorylation and stability. </p> <h2 id="function">Function</h2> <p>ROCK1 has a diverse range of functions in the body. It is a key regulator of actin-myosin contraction, stability, and <a href="/facts/Cell_polarity/epTfY0gK">cell polarity</a>.<a class="footnote-ref" id="fnref:31" href="#fn:31"><sup>31</sup></a> These contribute to many progresses such as regulation of morphology, gene transcription, proliferation, differentiation, apoptosis and oncogenic transformation.<a class="footnote-ref" id="fnref:32" href="#fn:32"><sup>32</sup></a> Other functions involve smooth muscle contraction, actin cytoskeleton organization, stress fiber and focal adhesion formation, <a href="/facts/Neurite/A1dzfEKy">neurite</a> retraction, <a href="/facts/Cell_adhesion/Vg4alzxb">cell adhesion</a> and motility. These functions are activated by phosphorylation of <a href="/facts/DAPK3/ARXCfFzu">DAPK3</a>, <a href="/facts/Glial_fibrillary_acidic_protein/3GXWrMay">GFAP</a>, <a href="/facts/LIMK1/6esH801p">LIMK1</a>, <a href="/facts/LIMK2/9rSzzSK7">LIMK2</a>, <a href="/facts/MYL9/n6AuhRA2">MYL9/MLC2</a>, <a href="/facts/PFN1/CzN4nxAB">PFN1</a> and <a href="/facts/PPP1R12A/vu7gToHE">PPP1R12A</a>.<a class="footnote-ref" id="fnref:33" href="#fn:33"><sup>33</sup></a> Additionally, ROCK1 phosphorylates <a href="/facts/FHOD1/n1bT7UjL">FHOD1</a> and acts synergistically with it to promote SRC-dependent non-apoptotic plasma membrane <a href="/facts/Bleb_(cell_biology)/NRLFYNR5">blebbing</a>.<a class="footnote-ref" id="fnref:34" href="#fn:34"><sup>34</sup></a> It is also required for centrosome positioning and centrosome-dependent exit from mitosis.<a class="footnote-ref" id="fnref:35" href="#fn:35"><sup>35</sup></a> </p> <h2 id="interactions">Interactions</h2> <p>ROCK1 has been shown to <a href="/facts/Protein-protein_interaction/etvm9Wmg">interact</a> with: </p> <ul><li><a href="/facts/LIMK1/6esH801p">LIMK1</a>,<a class="footnote-ref" id="fnref:36" href="#fn:36"><sup>36</sup></a></li> <li><a href="/facts/MLC1/NBmaFwdx">MLC</a>,<a class="footnote-ref" id="fnref:37" href="#fn:37"><sup>37</sup></a></li> <li><a href="/facts/PPP1R12A/vu7gToHE">MYPT1</a>,<a class="footnote-ref" id="fnref:38" href="#fn:38"><sup>38</sup></a></li> <li><a href="/facts/PFN2/QKcj2m1G">PFN2</a>,<a class="footnote-ref" id="fnref:39" href="#fn:39"><sup>39</sup></a> and</li> <li><a href="/facts/RHOA/qurgmh7r">RHOA</a>.<a class="footnote-ref" id="fnref:40" href="#fn:40"><sup>40</sup></a><a class="footnote-ref" id="fnref:41" href="#fn:41"><sup>41</sup></a><a class="footnote-ref" id="fnref:42" href="#fn:42"><sup>42</sup></a></li></ul> <h2 id="clinical-significance">Clinical significance</h2> <p>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.<a class="footnote-ref" id="fnref:43" href="#fn:43"><sup>43</sup></a> In addition, ROCK kinases influence more distal cellular processes including gene transcription, proliferation, differentiation, apoptosis and oncogenic transformation.<a class="footnote-ref" id="fnref:44" href="#fn:44"><sup>44</sup></a> Given this diverse range of functions, it is not surprising that ROCK1 has been implicated in numerous aspects of cancer.<a class="footnote-ref" id="fnref:45" href="#fn:45"><sup>45</sup></a> </p> <h3>Role in cancer</h3> <p>Recent studies have explored the role of ROCK1 in cancer with particular attention focused on cell motility, metastasis, and angiogenesis.<a class="footnote-ref" id="fnref:46" href="#fn:46"><sup>46</sup></a> Rho GTPases such as RhoA are highly involved in morphologic changes in cells. When a tumor progresses from invasive to metastatic form it requires that they undergo these dramatic morphologic changes. Therefore, increased expression of RhoA and its downstream effector ROCK1 is often observed in human cancers. These cancers are typically more invasive and metastatic phenotypes.<a class="footnote-ref" id="fnref:47" href="#fn:47"><sup>47</sup></a> </p> <h3>Angiogenesis</h3> <p>Increased expression of RhoA and ROCK1 in endothelial cell migration pathways can cause an increase in angiogenesis and metastatic behavior in tumor cells.<a class="footnote-ref" id="fnref:48" href="#fn:48"><sup>48</sup></a> It has been suggested that ROCK1 either regulates the expression of angiogenic factors or ROCK1 activation facilitates angiogenesis by increasing the plasticity of the tumor. By reducing the strength of cell-cell interactions and aiding the movement of tumor cells, ROCK1 may enable endothelial cells to penetrate the tumor mass more easily.<a class="footnote-ref" id="fnref:49" href="#fn:49"><sup>49</sup></a> </p> <h3>ROCK1 inhibitors in cancer therapy</h3> <p>ROCK1 inhibitors might be used in cancer therapy for: </p> <ul><li>targeting of <a href="/facts/Stromal_cells/31AA691H">stromal</a> rather than <a href="/facts/Tumor_cells/K0ytzmPz">tumor cells</a><a class="footnote-ref" id="fnref:50" href="#fn:50"><sup>50</sup></a></li> <li>concomitant blocking of ROCK and <a href="/facts/Proteasome/8vTtg2MI">proteasome</a> activity in <a href="/facts/KRAS/NSVQ0ALz">K‐Ras</a>‐driven lung cancers <a class="footnote-ref" id="fnref:51" href="#fn:51"><sup>51</sup></a></li> <li>treating haematological malignancies such as <a href="/facts/Chronic_myelogenous_leukemia/FA9TdgQn">chronic myelogenous leukemia</a> (CML)<a class="footnote-ref" id="fnref:52" href="#fn:52"><sup>52</sup></a></li></ul> <p>ROCK1 inhibition for cancer treatment has not been approved for standard therapy use. <a href="/facts/Y27632/BB5FQ1JP">Y27632</a> and <a href="/facts/Fasudil/Ut3K8QDd">Fasudil</a> are examples of ROCK1 inhibitors. Both inhibit ROCK1 by competing with <a href="/facts/Adenosine_triphosphate/nB9bwgcU">ATP</a> for the kinase activation site. Experiments with Y27632 show it is a promising candidate as a therapeutic <a href="/facts/Antihypertensive_drug/K63MbxN0">antihypertensive agent</a>.<a class="footnote-ref" id="fnref:53" href="#fn:53"><sup>53</sup></a> Fasudil has been used to characterize the role of ROCK1 in vascular function in clinical studies and has been approved for use in Japan for treatment of <a href="/facts/Cerebral_vasospasm/oTyemSUA">cerebral vasospasm</a> following <a href="/facts/Subarachnoid_hemorrhage/otbJ6CcK">subarachnoid hemorrhage</a>.<a class="footnote-ref" id="fnref:54" href="#fn:54"><sup>54</sup></a> </p> <h3>Other diseases</h3> <p>The ROCK1 signaling plays an important role in many diseases including <a href="/facts/Diabetes/2xeHXbsI">diabetes</a>, <a href="/facts/Neurodegenerative_diseases/HTDrVEqc">neurodegenerative diseases</a> such as <a href="/facts/Parkinson%2527s_disease/xpekKj6x">Parkinson's disease</a> and <a href="/facts/Amyotrophic_lateral_sclerosis/9fIXnNL4">amyotrophic lateral sclerosis</a> (ALS),<a class="footnote-ref" id="fnref:55" href="#fn:55"><sup>55</sup></a> and <a href="/facts/Pulmonary_hypertension/4848aBJl">pulmonary hypertension</a>.<a class="footnote-ref" id="fnref:56" href="#fn:56"><sup>56</sup></a> </p> <h2 id="see-also">See also</h2> <ul><li><a href="/facts/Rho_kinase/cqhYf4t4">Rho kinase</a></li></ul> <h2 id="further-reading">Further reading</h2> <ul><li>Riento K, Ridley AJ (June 2003). "Rocks: multifunctional kinases in cell behaviour". <i>Nature Reviews. Molecular Cell Biology</i>. 4 (6): 446–456. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1038%2Fnrm1128">10.1038/nrm1128</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/12778124">12778124</a>. <a href="/facts/S2CID_(identifier)/ldJsHa2Y">S2CID</a> <a href="https://api.semanticscholar.org/CorpusID:40665081">40665081</a>.</li></ul> <h2 id="external-links">External links</h2> <ul><li><a href="https://web.archive.org/web/20110722012837/http://cmkb.cellmigration.org/report.cgi?report=orth_overview&gene_id=6093">ROCK1</a> Info with links in the <a href="http://www.cellmigration.org/index.shtml">Cell Migration Gateway</a> <a href="https://web.archive.org/web/20141211173306/http://www.cellmigration.org/index.shtml">Archived</a> 2014-12-11 at the <a href="/facts/Wayback_Machine/nmQ3a6JC">Wayback Machine</a></li></ul> <h2 id="references">References</h2> <ol> <li id="fn:1"><p>Rath N, Olson MF (October 2012). "Rho-associated kinases in tumorigenesis: re-considering ROCK inhibition for cancer therapy". EMBO Reports. 13 (10): 900–908. doi:10.1038/embor.2012.127. PMC 3463970. PMID 22964758. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3463970" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3463970</a> <a href="#fnref:1" class="footnote-back-ref">↩</a></p></li> <li id="fn:2"><p>Rath N, Olson MF (October 2012). "Rho-associated kinases in tumorigenesis: re-considering ROCK inhibition for cancer therapy". EMBO Reports. 13 (10): 900–908. doi:10.1038/embor.2012.127. PMC 3463970. PMID 22964758. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3463970" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3463970</a> <a href="#fnref:2" class="footnote-back-ref">↩</a></p></li> <li id="fn:3"><p>"ROCK1 Rho-associated, coiled-coil containing protein kinase 1 [ Homo sapiens (human) ]". <a href="https://www.ncbi.nlm.nih.gov/gene/6093" target="_blank">https://www.ncbi.nlm.nih.gov/gene/6093</a> <a href="#fnref:3" class="footnote-back-ref">↩</a></p></li> <li id="fn:4"><p>"Rho-Associated, Coiled-Coil Containing Protein Kinase 1". <a href="https://www.genecards.org/cgi-bin/carddisp.pl?gene=ROCK1" target="_blank">https://www.genecards.org/cgi-bin/carddisp.pl?gene=ROCK1</a> <a href="#fnref:4" class="footnote-back-ref">↩</a></p></li> <li id="fn:5"><p>"Rho-Associated, Coiled-Coil Containing Protein Kinase 1". <a href="https://www.genecards.org/cgi-bin/carddisp.pl?gene=ROCK1" target="_blank">https://www.genecards.org/cgi-bin/carddisp.pl?gene=ROCK1</a> <a href="#fnref:5" class="footnote-back-ref">↩</a></p></li> <li id="fn:6"><p>Hahmann C, Schroeter T (January 2010). "Rho-kinase inhibitors as therapeutics: from pan inhibition to isoform selectivity". Cellular and Molecular Life Sciences. 67 (2): 171–177. doi:10.1007/s00018-009-0189-x. PMC 11115778. PMID 19907920. S2CID 6445354. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11115778" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11115778</a> <a href="#fnref:6" class="footnote-back-ref">↩</a></p></li> <li id="fn:7"><p>Riento K, Ridley AJ (June 2003). "Rocks: multifunctional kinases in cell behaviour". Nature Reviews. Molecular Cell Biology. 4 (6): 446–456. doi:10.1038/nrm1128. PMID 12778124. S2CID 40665081. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:7" class="footnote-back-ref">↩</a></p></li> <li id="fn:8"><p>Nakagawa O, Fujisawa K, Ishizaki T, Saito Y, Nakao K, Narumiya S (August 1996). "ROCK-I and ROCK-II, two isoforms of Rho-associated coiled-coil forming protein serine/threonine kinase in mice". FEBS Letters. 392 (2): 189–193. Bibcode:1996FEBSL.392..189N. doi:10.1016/0014-5793(96)00811-3. PMID 8772201. S2CID 6684411. <a href="https://doi.org/10.1016%2F0014-5793%2896%2900811-3" target="_blank">https://doi.org/10.1016%2F0014-5793%2896%2900811-3</a> <a href="#fnref:8" class="footnote-back-ref">↩</a></p></li> <li id="fn:9"><p>"Rho-Associated, Coiled-Coil Containing Protein Kinase 1". <a href="https://www.genecards.org/cgi-bin/carddisp.pl?gene=ROCK1" target="_blank">https://www.genecards.org/cgi-bin/carddisp.pl?gene=ROCK1</a> <a href="#fnref:9" class="footnote-back-ref">↩</a></p></li> <li id="fn:10"><p>"Rho Kinase in Vascular Smooth Muscle". Chapter 7Rho Kinase in Vascular Smooth Muscle. Morgan & Claypool Life Sciences. 2010. <a href="https://www.ncbi.nlm.nih.gov/books/NBK54588/#sec41" target="_blank">https://www.ncbi.nlm.nih.gov/books/NBK54588/#sec41</a> <a href="#fnref:10" class="footnote-back-ref">↩</a></p></li> <li id="fn:11"><p>"Rho Kinase in Vascular Smooth Muscle". Chapter 7Rho Kinase in Vascular Smooth Muscle. Morgan & Claypool Life Sciences. 2010. <a href="https://www.ncbi.nlm.nih.gov/books/NBK54588/#sec41" target="_blank">https://www.ncbi.nlm.nih.gov/books/NBK54588/#sec41</a> <a href="#fnref:11" class="footnote-back-ref">↩</a></p></li> <li id="fn:12"><p>"Rho Kinase in Vascular Smooth Muscle". Chapter 7Rho Kinase in Vascular Smooth Muscle. Morgan & Claypool Life Sciences. 2010. <a href="https://www.ncbi.nlm.nih.gov/books/NBK54588/#sec41" target="_blank">https://www.ncbi.nlm.nih.gov/books/NBK54588/#sec41</a> <a href="#fnref:12" class="footnote-back-ref">↩</a></p></li> <li id="fn:13"><p>Jacobs M, Hayakawa K, Swenson L, Bellon S, Fleming M, Taslimi P, et al. (January 2006). "The structure of dimeric ROCK I reveals the mechanism for ligand selectivity". The Journal of Biological Chemistry. 281 (1): 260–268. doi:10.1074/jbc.M508847200. 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