Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:2.7.12.2 (
MEK
)
18,161
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
The interconnected PI3K and MAPK signaling pathways are commonly perturbed in cancer. Dual inhibition of these pathways by the small-molecule PI3K inhibitor pictilisib (GDC-0941) and the
MEK
inhibitor cobimetinib (GDC-0973) suppresses cell proliferation and induces cell death better than either single agent in several preclinical models. Using mass spectrometry-based phosphoproteomics, we have identified the RING finger E3 ubiquitin ligase
RNF157
as a target at the intersection of PI3K and MAPK signaling. We demonstrate that
RNF157
phosphorylation downstream of the PI3K and MAPK pathways influences the ubiquitination and stability of
RNF157
during the cell cycle in an anaphase-promoting complex/cyclosome-CDH1-dependent manner. Deletion of these phosphorylation-targeted residues on
RNF157
disrupts binding to CDH1 and protects
RNF157
from ubiquitination and degradation. Expression of the cyclin-dependent kinase 2 (CDK2), itself a downstream target of PI3K/MAPK signaling, leads to increased phosphorylation of
RNF157
on the same residues modulated by PI3K and MAPK signaling. Inhibition of PI3K and
MEK
in combination or of CDK2 by their respective small-molecule inhibitors reduces
RNF157
phosphorylation at these residues and attenuates
RNF157
interaction with CDH1 and its subsequent degradation. Knockdown of endogenous
RNF157
in melanoma cells leads to late S phase and G
2
/M arrest and induces apoptosis, the latter further potentiated by concurrent PI3K/
MEK
inhibition, consistent with a role for
RNF157
in the cell cycle. We propose that
RNF157
serves as a novel node integrating oncogenic signaling pathways with the cell cycle machinery and promoting optimal cell cycle progression in transformed cells.
...
PMID:Role of the E3 ubiquitin ligase RNF157 as a novel downstream effector linking PI3K and MAPK signaling pathways to the cell cycle. 2865 64
