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2017 ; 31
(17
): 1809-1820
Nephropedia Template TP
Yue J
; Lai F
; Beckedorff F
; Zhang A
; Pastori C
; Shiekhattar R
Genes Dev
2017[Sep]; 31
(17
): 1809-1820
PMID28982763
show ga
Activating mutations in the mitogen-activated protein kinase (MAPK) cascade, also
known as the RAS-MEK-extracellular signal-related kinase (ERK1/2) pathway, are an
underlying cause of >70% of human cancers. While great strides have been made
toward elucidating the cytoplasmic components of MAPK signaling, the key
downstream coactivators that coordinate the transcriptional response have not
been fully illustrated. Here, we demonstrate that the MAPK transcriptional
response in human cells is funneled through Integrator, an RNA polymerase
II-associated complex. Integrator depletion diminishes ERK1/2 transcriptional
responsiveness and cellular growth in human cancers harboring activating
mutations in MAPK signaling. Pharmacological inhibition of the MAPK pathway
abrogates the stimulus-dependent recruitment of Integrator at immediate early
genes and their enhancers. Following epidermal growth factor (EGF) stimulation,
activated ERK1/2 is recruited to immediate early genes and phosphorylates INTS11,
the catalytic subunit of Integrator. Importantly, in contrast to the broad
effects of Integrator knockdown on MAPK responsiveness, depletion of a number of
critical subunits of the coactivator complex Mediator alters only a few
MAPK-responsive genes. Finally, human cancers with activating mutations in the
MAPK cascade, rendered resistant to targeted therapies, display diminished growth
following depletion of Integrator. We propose Integrator as a crucial
transcriptional coactivator in MAPK signaling, which could serve as a downstream
therapeutic target for cancer treatment.
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