# Defining protein interaction networks involving the atypical MAP kinases ERK4 and ERK7

> **NIH NIH R03** · YALE UNIVERSITY · 2022 · $159,906

## Abstract

ABSTRACT
Mitogen-activated protein kinases (MAPKs) are core components of signaling networks activated in response to
a variety of cellular stimuli. Classical MAPKs in the ERK1/2, p38, JNK and ERK5 families are situated in three-
tiered kinase cascades and have been intensely studied. In contrast, several “atypical” members of the MAPK
family do not participate in canonical MAPK cascades, and we know comparatively little about how they function.
In particular, while hundreds of substrates have been identified for classical MAPKs, only a few downstream
targets are known for the most understudied atypical MAPKs, ERK4 (MAPK4) and ERK7 (MAPK15). Here we
propose to exploit basic mechanisms of MAPK substrate targeting to identify new ERK4 and ERK7 interactors
and substrates. Classical MAPKs are established to interact with short linear sequence motifs in their substrates
and regulators through a “docking groove” within the kinase domain separate from the catalytic cleft. While ERK4
and ERK7 appear to have an analogous docking groove, we have no knowledge of sequence motifs targeted by
these kinases. In unpublished studies, we have developed a yeast-based screening platform that we will apply
to discover human proteome-derived peptide sequences that interact with the docking grooves of ERK4 and
ERK7. We will validate results from these screens by determining MAPK binding affinities for a panel of hit
peptides and their variants. We will subsequently investigate whether full length proteins corresponding to hits
from our screens constitute authentic ERK4 or ERK7 interaction partners and/or substrates. We will perform in
vitro kinase assays to determine whether the MAPKs phosphorylate these candidate substrates in a manner
dependent on their docking groove and examine whether hit proteins associate with the MAPKs in cultured cells.
Finally, we will examine whether CRISPR/Cas9-mediated kinase knockout or mutation of the substrate docking
sequence disrupts phosphorylation of candidate substrates. Through these studies, we aim to discover new
substrates and regulators of ERK4 and ERK7, thereby providing mechanistic insight into how they function and
potentially identifying new biological processes under their control.

## Key facts

- **NIH application ID:** 10451068
- **Project number:** 1R03TR004173-01
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** BENJAMIN E TURK
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $159,906
- **Award type:** 1
- **Project period:** 2022-06-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10451068

## Citation

> US National Institutes of Health, RePORTER application 10451068, Defining protein interaction networks involving the atypical MAP kinases ERK4 and ERK7 (1R03TR004173-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10451068. Licensed CC0.

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