# Elucidating the Role of Src and JNK signaling in Net1A-dependent Breast Cancer Metastasis

> **NIH NIH F31** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2020 · $32,699

## Abstract

Project Summary
Breast cancer metastasis kills over 40,000 women annually and there are very few therapies that efficiently
target this process. A hallmark of breast cancer metastasis is an increase in cancer cell migration and invasion,
which is driven in part by the small GTPase RhoA. Unfortunately, therapeutic targeting of RhoA has not been
successful because it is expressed ubiquitously throughout the body and has no targetable interfaces. The
neuroepithelial transforming gene 1 (Net1), is a Rho guanine exchange factor (RhoGEF) that is overexpressed
in breast cancer and is required for breast cancer cell motility. Net1 isoforms are uniquely regulated by nuclear
sequestration. However, ligand stimulation of quiescent cells allows the Net1A isoform to relocalize to the
cytoplasm, where it can activate RhoA. Recent work from our lab has established c-Jun-N-terminal kinase
(JNK) and Src signaling are required for ligand stimulated cytosolic localization of Net1A, and that these
kinases phosphorylate distinct sites within Net1A to cause this effect. Based on these findings, we
hypothesize that Src cooperates with JNK to regulate Net1A cytoplasmic accumulation to promote
breast cancer motility and metastasis. In Aim 1, we will determine how Src-dependent phosphorylation of
Net1A on Y373 controls its subcellular localization. We will identify the kinase that directly phosphorylates
Net1A on this site, and elucidate the mechanism by which this drives Net1A nuclear export. In Aim 2 we will
determine how JNK and Src signaling synergize to promote cytoplasmic accumulation of Net1A to stimulate
RhoA activation and breast cancer cell motility in vitro. In Aim 3, we will establish the role of JNK- and Src-
dependent phosphorylation of Net1A in mammary gland tumorigenesis and metastasis using orthotopic
mammary tumor models. We hypothesize these signaling events to be key drivers of Net1A-mediated motility
and invasion. Identification of these regulatory mechanisms may provide novel therapeutic approaches to
mitigate breast cancer metastasis.

## Key facts

- **NIH application ID:** 9961507
- **Project number:** 5F31CA232634-03
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** Ashabari Mukherjee
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $32,699
- **Award type:** 5
- **Project period:** 2018-08-01 → 2021-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9961507

## Citation

> US National Institutes of Health, RePORTER application 9961507, Elucidating the Role of Src and JNK signaling in Net1A-dependent Breast Cancer Metastasis (5F31CA232634-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9961507. Licensed CC0.

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