# Control of actin filament networks by Arp2/3 complex and its regulators

> **NIH NIH R35** · UNIVERSITY OF OREGON · 2021 · $565,818

## Abstract

Summary
To orchestrate complex processes like motility and endocytosis, cells rely on regulatory proteins that control the
dynamics and architectures of the actin cytoskeleton. Actin filament nucleators are important actin regulators
because they allow cells to control the initiation of new actin networks and dictate the architectures of these
networks. Arp2/3 complex is a seven subunit actin filament nucleating machine that specifically generates
branched actin filaments. Regulated branching by Arp2/3 complex is important not only for processes
required for normal cellular function, such as endocytosis and protrusion of lamellipodia, but also in pathogenic
processes like host cell infection by bacteria or metastasis of tumor cells. The majority of studies on Arp2/3
complex regulation have focused on WASP proteins, an activator that mediates propagation of branched actin
networks. These studies revealed the basic tenets of WASP mediated activation; that WASP binds to Arp2/3
complex, recruits actin monomers, and stimulates an activating conformational change. However, the
molecular aspects of WASP mediated-activation most important for understanding the biological function of the
complex are still unknown. For instance, it is unknown why WASP proteins require actin filaments to activate
Arp2/3 complex, a requirement that allows Arp2/3 complex to function specifically as a branched actin filament
nucleator. Further, it is not known why WASP (but not other activators) must recruit actin monomers to Arp2/3
complex to trigger nucleation, despite the fact that this requirement regulates the density of branched filament
ends in Arp2/3-assembled actin networks. In addition to WASP, several other regulatory proteins are now
known to activate Arp2/3 complex. We recently discovered that the WISH/DIP/SPIN90 (WDS) proteins are
distinct from WASP in that they can activate Arp2/3 complex without preformed filaments to induce it to
nucleate linear actin filaments. These linear filaments serve as seeds to kickstart WASP-mediated branching
thereby initiating actin network assembly. Despite the fact that initiation is perhaps the most important
step in controlling branched network assembly, how WDS proteins activate the complex to create seed
filaments is unknown. Furthermore, it is not understood how the activity of WDS proteins is coordinated with
other activators like WASP, or how WDS proteins themselves are regulated. Here we propose a combination of
biochemical, biophysical, structural, computational, and cell biological approaches to investigate these
questions, with a long-term goal of understanding how these regulatory mechanisms allow Arp2/3 complex to
control actin dynamics in complex cellular processes.

## Key facts

- **NIH application ID:** 10137962
- **Project number:** 5R35GM136319-02
- **Recipient organization:** UNIVERSITY OF OREGON
- **Principal Investigator:** Bradley J Nolen
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $565,818
- **Award type:** 5
- **Project period:** 2020-05-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10137962

## Citation

> US National Institutes of Health, RePORTER application 10137962, Control of actin filament networks by Arp2/3 complex and its regulators (5R35GM136319-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10137962. Licensed CC0.

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