Small molecules discovered in a pathway screen target the Rho pathway in cytokinesis.
We report the discovery of small molecules that target the Rho pathway, which is a central regulator of cytokinesis--the final step in cell division. We have developed a way of targeting a small molecule screen toward a specific pathway, which should be widely applicable to the investigation of any signaling pathway. In a chemical genetic variant of a classical modifier screen, we used RNA interference (RNAi) to sensitize cells and identified small molecules that suppressed or enhanced the RNAi phenotype. We discovered promising candidate molecules, which we named Rhodblock, and we identified the target of Rhodblock as Rho kinase. Several Rhodblocks inhibited one function of the Rho pathway in cells: the correct localization of phosphorylated myosin light chain during cytokinesis. Rhodblocks differentially perturb Rho pathway proteins in cells and can be used to dissect the mechanism of the Rho pathway during cytokinesis.
Castoreno
Adam B
AB
Dana-Farber Cancer Institute and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.
Smurnyy
Yegor
Y
Torres
Angelica D
AD
Vokes
Martha S
MS
Jones
Thouis R
TR
Carpenter
Anne E
AE
Eggert
Ulrike S
US
D000818:Animals; D048749:Cytokinesis / Q000187:drug effects / Q000502:physiology*; D004330:Drosophila / Q000201:enzymology / Q000235:genetics / Q000502:physiology; D029721:Drosophila Proteins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020558:GTP Phosphohydrolases / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000378:metabolism; D006153:Guanosine Diphosphate / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D007089:Image Enhancement; D007700:Kinetics; D024462:Myosin Type II / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D012313:RNA / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*
D029721:Drosophila Proteins; D004791:Enzyme Inhibitors; D020690:GTPase-Activating Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; C502951:tum protein, Drosophila; D006153:Guanosine Diphosphate; D012313:RNA; D006160:Guanosine Triphosphate; D054460:rho-Associated Kinases; D020558:GTP Phosphohydrolases; D024462:Myosin Type II