title: MgcRacGAP inhibition stimulates JAK-dependent STAT3 activity.
abstract: Male germ cell Rac GTPase-activating protein (MgcRacGAP) is a core regulator of cytokinesis. Furthermore, it appears to be involved in human oncogenesis through cytokinesis-independent mechanisms and has been reported to be essential for nuclear translocation of signal transducer and activator of transcription (STAT) proteins, including the oncoprotein STAT3. Here we utilized MgcRacGAP inhibitor compound 1 (MINC1), a small molecule inhibitor of MgcRacGAP, to further investigate how MgcRacGAP regulates STAT3. Surprisingly, both MINC1 treatment and small interference RNA (siRNA)-mediated gene silencing of MgcRacGAP resulted in increased STAT3 phosphorylation and STAT3-driven transcriptional activity in our experimental systems. Finally, we demonstrated that MINC1-induced STAT3 activation likely is due to increased STAT3 phosphorylation caused by a Rac1-PAR3-IL6-IL6R-JAK2 mediated autocrine/paracrine mechanism.
authors.affiliation: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland. Electronic address: arnoldus.adrichem@fimm.fi.
authors.forename: Arjan J
authors.initials: AJ
authors.lastname: van Adrichem
authors.affiliation: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
authors.forename: Krister
authors.initials: K
authors.lastname: Wennerberg
mesh_terms: D004305:Dose-Response Relationship, Drug; D020690:GTPase-Activating Proteins / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics; D020868:Gene Silencing; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D053614:Janus Kinase 2 / Q000378:metabolism; D053612:Janus Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D034741:RNA, Small Interfering / Q000235:genetics; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D014443:Tyrosine / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D020690:GTPase-Activating Proteins; D034741:RNA, Small Interfering; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor; C115995:mgcRacGAP; D014443:Tyrosine; D053614:Janus Kinase 2; D053612:Janus Kinases; D020830:rac1 GTP-Binding Protein
keywords: Activation; Male germ cell Rac GTPase-activating protein; Nuclear translocation; Signal transducer and activator of transcription 3; Small molecule inhibitor