# Adaptor protein function in breast cancer

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2020 · $386,917

## Abstract

Project Summary
The overall goal of this proposal is to determine the mechanism by which Insulin Receptor Substrate 2 (IRS2)
promotes invasion and its role in breast cancer. IRS2 is a cytoplasmic adaptor protein that is a key signaling
effector of the insulin (IR) and insulin-like growth factor-1 (IGF1R) receptors, both of which have been implicated
in breast cancer. Mouse mammary tumors that lack Irs2 are significantly diminished in their ability to metastasize
and tumors with elevated Irs2 expression have enhanced tumor growth and metastatic potential. Work from the
applicant’s lab has established that IRS2 promotes invasion, an early step in the dissemination of metastatic
cells to secondary organs. The significance of IRS2 promoting invasion is heightened by the applicant’s recent
discovery that IRS2 is recurrently mutated in pleomorphic invasive lobular carcinoma (PILC), an aggressive,
metastatic breast cancer subtype. Importantly, the mechanism by which IRS2 integrates upstream signals to
mediate its functional outcomes remains unknown. Determining how IRS2 regulates invasion requires an
understanding of its structure, and how this structure determines function. The applicant’s preliminary data
establish that the ability of IRS2 to promote invasion is dependent upon upstream IGF1R/IR activation and the
recruitment and activation of PI3K. In addition, they identified a 174-amino acid region within the IRS2 C-terminal
tail that is required for invasion. Importantly, this region is not required for the IRS2-dependent regulation of
glucose uptake, revealing that these two functions of IRS2 are independently regulated. Essential interactions
likely occur within this region given that it acts in a dominant negative manner to inhibit invasion. To investigate
the hypothesis that the structure of IRS2 is dynamically altered by upstream stimuli that promote invasion to
facilitate binding of essential downstream signaling effectors the applicant will: 1) Define the structural basis for
IRS2-mediated invasion and signaling. The hypothesis that specific sequences within IRS2 participate in
dynamic intramolecular interactions that alter protein conformation and signaling to promote invasion will be
examined; 2) Investigate IRS2 interacting partners and their role in promoting invasion. The hypothesis that
intramolecular interactions within IRS2 lead to the formation of “disordered domain” loops that assemble distinct
signaling sub-complexes to mediate functional outcomes, and that one of these binding proteins is the serine
threonine kinase BMP2K, will be examined; 3) Establish the role of IRS2-dependent invasion in breast cancer
progression in vivo. The hypothesis that selective targeting of IRS2-dependent invasion will reveal an essential
role for this specific function in breast cancer progression will be examined. The contribution of IRS2 mutations
to PILC progression will also be examined.

## Key facts

- **NIH application ID:** 9889069
- **Project number:** 5R01CA229910-02
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** LESLIE M SHAW
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $386,917
- **Award type:** 5
- **Project period:** 2019-03-07 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9889069

## Citation

> US National Institutes of Health, RePORTER application 9889069, Adaptor protein function in breast cancer (5R01CA229910-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9889069. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*