| First Author | Ohm AM | Year | 2019 |
| Journal | J Biol Chem | Volume | 294 |
| Issue | 12 | Pages | 4488-4497 |
| PubMed ID | 30679314 | Mgi Jnum | J:276809 |
| Mgi Id | MGI:6307637 | Doi | 10.1074/jbc.RA118.006944 |
| Citation | Ohm AM, et al. (2019) EGF receptor and PKCdelta kinase activate DNA damage-induced pro-survival and pro-apoptotic signaling via biphasic activation of ERK and MSK1 kinases. J Biol Chem 294(12):4488-4497 |
| abstractText | DNA damage-mediated activation of extracellular signal-regulated kinase (ERK) can regulate both cell survival and cell death. We show here that ERK activation in this context is biphasic and that early and late activation events are mediated by distinct upstream signals that drive cell survival and apoptosis, respectively. We identified the nuclear kinase mitogen-sensitive kinase 1 (MSK1) as a downstream target of both early and late ERK activation. We also observed that activation of ERK-->MSK1 up to 4 h after DNA damage depends on epidermal growth factor receptor (EGFR), as EGFR or mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK)/ERK inhibitors or short hairpin RNA-mediated MSK1 depletion enhanced cell death. This prosurvival response was partially mediated through enhanced DNA repair, as EGFR or MEK/ERK inhibitors delayed DNA damage resolution. In contrast, the second phase of ERK-->MSK1 activation drove apoptosis and required protein kinase Cdelta (PKCdelta) but not EGFR. Genetic disruption of PKCdelta reduced ERK activation in an in vivo irradiation model, as did short hairpin RNA-mediated depletion of PKCdelta in vitro In both models, PKCdelta inhibition preferentially suppressed late activation of ERK. We have shown previously that nuclear localization of PKCdelta is necessary and sufficient for apoptosis. Here we identified a nuclear PKCdelta-->ERK-->MSK1 signaling module that regulates apoptosis. We also show that expression of nuclear PKCdelta activates ERK and MSK1, that ERK activation is required for MSK1 activation, and that both ERK and MSK1 activation are required for apoptosis. Our findings suggest that location-specific activation by distinct upstream regulators may enable distinct functional outputs from common signaling pathways. |
