title: ROCK1 feedback regulation of the upstream small GTPase RhoA.
abstract: Rho-associated coiled-coil containing protein kinase 1 (ROCK1) is a key downstream effector of the small GTPase RhoA. Targeting ROCK1 has shown promising clinical potential in cancer, cardioprotection, hypertension, diabetes, neuronal regeneration, and stem cell biology. General working hypothesis in previous studies has centered on the function of ROCK1 as a downstream sequence in the RhoA signaling pathway. In this study, the effects of the direct inhibition of ROCK1 on the activity of upstream RhoA and Rac1 were examined using a combined pharmacological and genetic approach. We report an intriguing mechanism by which the inhibition of ROCK1 indirectly diminishes the activity of upstream RhoA through the stimulation of Tiam1-induced Rac1 activity. This novel feedback mechanism, in which ROCK1 mediates upstream Rac1 and RhoA activity, offers considerable insight into the diverse effects of ROCK1 on the functional balance of the Rho family of small GTPases, which regulates actin cytoskeleton reorganization processes and the resulting overall behavior of cells.
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, United States.
authors.forename: Alan T
authors.initials: AT
authors.lastname: Tang
authors.forename: William B
authors.initials: WB
authors.lastname: Campbell
authors.forename: Kasem
authors.initials: K
authors.lastname: Nithipatikom
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D036002:ADP Ribose Transferases / Q000494:pharmacology; D008841:Actin Cytoskeleton / Q000235:genetics / Q000378:metabolism; D000577:Amides / Q000494:pharmacology; D000634:Aminoquinolines / Q000494:pharmacology; D001905:Botulinum Toxins / Q000494:pharmacology; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation / Q000187:drug effects; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism; D054460:rho-Associated Kinases / Q000235:genetics / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D000577:Amides; D000634:Aminoquinolines; D020662:Guanine Nucleotide Exchange Factors; C487513:NSC 23766; D011725:Pyridines; D011743:Pyrimidines; C107953:RAC1 protein, human; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; C087334:TIAM1 protein, human; C122170:TIAM2 protein, human; C066737:RHOA protein, human; C108830:Y 27632; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D036002:ADP Ribose Transferases; C063007:exoenzyme C3, Clostridium botulinum; C515851:ROCK1 protein, human; D054460:rho-Associated Kinases; D001905:Botulinum Toxins; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein; C049347:fasudil