# Mitogenic and Oncogenic Regulation of ERK/RSK Signaling

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2021 · $682,680

## Abstract

Project Summary
It is estimated that approximately 90% of cancer mortality is the result of cancer cells gaining the ability to leave
the primary tumor, activate survival mechanisms, invade surrounding tissues, enter the circulation and then exit
by migrating into new tissues where they may form metastatic tumors, often after long latencies. Therefore,
defining the signaling mechanisms that contribute to altered growth, metabolism, motility and survival associated
with metastasis, are of critical importance. Our goal is to uncover the molecular basis of these signaling events
using biochemical, cell biological and genetic approaches. It is well established that the Ras-MAP kinase/ERK
pathway plays a role in most aspects of cancer cell biology. However, it remains unclear how ERK signaling can
generate different cell fates. We have revealed the importance of subtle differences in ERK signal strength,
location and duration as critical determinants of cellular outcomes. Additionally, we have more recently
demonstrated that different ERK isoforms promote different cell fates. For example, ERK2 but not ERK1, plays
a major role in promoting the epithelial to mesenchymal transition (EMT). Furthermore, we have found that
different ERK2 docking domains, the CD domain and the DEF binding pocket (DBP), also regulate different
cellular outcomes. Whereas low level, sustained wild type ERK2 activity promotes EMT, we discovered that
ERK2 with CD domain mutations, which have been identified in several cancers and which signal through its
DBP, robustly promotes the development of the EMT phenotype. This is the result of gain-of-function positive
EMT signaling via the DBP and loss-of-function of negative inputs into EMT via the CD domain. It is therefore of
critical importance to determine how ERK2 signaling promotes EMT and metastatic behavior. Understanding
these mechanisms are part of the long-term goal of our basic research efforts to discover new potential targets
and identify new biomarkers, and to help resolve this currently unmet clinical need of targeting the metastatic
process. Thus, this grant proposes to investigate three novel areas associated with EMT and metastatic
behavior and to take advantage of discoveries made during the previous funding period. In aim 1, we will
investigate a unique connection between ERK2 and the histone H3.3 chaperone HIRA, how this regulates
chromatin remodeling, and how this contributes to EMT in cells and in in vivo models. In aim 2, we will define
the molecular basis for new links between ERK2 and the TGFb pathway as collaborators in the EMT process. In
aim 3, we will define how ERK2 alters the metabolic landscape associated with EMT and determine how critical
enzymes involved in a previously unknown link between amino acid metabolism and EMT are regulated and
contribute to the invasive phenotype. In conclusion, there is an essential need for greater understanding of the
mechanisms associated with EMT and metastatic beha...

## Key facts

- **NIH application ID:** 10173650
- **Project number:** 5R01CA046595-34
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** JOHN BLENIS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $682,680
- **Award type:** 5
- **Project period:** 1988-02-08 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10173650

## Citation

> US National Institutes of Health, RePORTER application 10173650, Mitogenic and Oncogenic Regulation of ERK/RSK Signaling (5R01CA046595-34). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10173650. Licensed CC0.

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