TY - JOUR
T1 - MgcRacGAP inhibition stimulates JAK-dependent STAT3 activity
AU - van Adrichem, Arjan J
AU - Wennerberg, Krister
N1 - Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
PY - 2015/12/21
Y1 - 2015/12/21
N2 - 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.
AB - 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.
KW - Dose-Response Relationship, Drug
KW - GTPase-Activating Proteins/antagonists & inhibitors
KW - Gene Silencing
KW - HEK293 Cells
KW - HeLa Cells
KW - Humans
KW - Janus Kinase 2/metabolism
KW - Janus Kinases/metabolism
KW - Phosphorylation/drug effects
KW - RNA, Small Interfering/genetics
KW - Receptors, Interleukin-6/metabolism
KW - STAT3 Transcription Factor/chemistry
KW - Signal Transduction/drug effects
KW - Transcription, Genetic/drug effects
KW - Tyrosine/metabolism
KW - rac1 GTP-Binding Protein/metabolism
U2 - 10.1016/j.febslet.2015.11.013
DO - 10.1016/j.febslet.2015.11.013
M3 - Journal article
C2 - 26602080
SN - 0014-5793
VL - 589
SP - 3859
EP - 3865
JO - F E B S Letters
JF - F E B S Letters
IS - 24 Pt B
ER -