Differential cleavage of Mst1 by caspase-7/-3 is responsible for TRAIL-induced activation of the MAPK superfamily.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been shown to induce apoptosis through caspase activation in a number of cancer cell lines while displaying minimal or no toxicity on normal cells, suggesting that this protein may hold potential for development as a new cancer therapeutic agent. Moreover, TRAIL can activate mitogen-activated protein kinases (MAPKs) in addition to caspases. However, it has not been clearly understood how MAPKs are activated by TRAIL and the biological significance of their activation. Here we show that TRAIL-induced MAPKs activation is dependent on caspase activation and that mammalian sterile 20-like kinase 1 (Mst1) functions as a mediator between caspase activation and MAPKs activation. Activation of MAPKs (JNK, p38, ERK) is differentially regulated by cleavage size (40 kDa and 36 kDa) of Mst1, which is controlled by caspase-7 and -3.
Song
Jae J
JJ
Department of Surgery and Pharmacology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
Lee
Yong J
YJ
D001483:Base Sequence; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism*; D053179:Caspase 7 / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D017931:DNA Primers / Q000235:genetics; D005260:Female; D017228:Hepatocyte Growth Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology; D008297:Male; D016297:Mutagenesis, Site-Directed; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D017384:Sequence Deletion; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D014162:Transfection
D017931:DNA Primers; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C082332:macrophage stimulating protein; D017228:Hepatocyte Growth Factor; C505407:CASP3 protein, human; C505520:CASP7 protein, human; D053148:Caspase 3; D053179:Caspase 7