Integrator orchestrates RAS/ERK1/2 signaling transcriptional programs

Jingyin Yue, Fan Lai, Felipe Beckedorff, Anda Zhang, Chiara Pastori, Ramin Shiekhattar

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

Activating mutations in the mitogen-activated protein kinase (MAPK) cascade, also known as the RAS–MEK–ex-tracellular 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 phosphor-ylates 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.

Original languageEnglish (US)
Pages (from-to)1809-1820
Number of pages12
JournalGenes and Development
Volume31
Issue number17
DOIs
StatePublished - Sep 1 2017

Keywords

  • ERK1/2
  • Epidermal growth factor
  • Immediate early genes
  • Integrator
  • MAPK signaling pathway

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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