# Regulation of cell migration and signaling by phosphotyrosine and ubiquitin

> **NIH NIH R01** · FRED HUTCHINSON CANCER RESEARCH CENTER · 2021 · $369,600

## Abstract

ABSTRACT
Protein tyrosine kinases (PTKs) phosphorylate tyrosine in proteins involved in cell signaling pathways that
stimulate cell migration, proliferation and oncogenic transformation. Phosphotyrosine (pY) proteins may be
inactivated by dephosphorylation or by proteasomal degradation following ubiquitylation by pY-specific
ubiquitin E3 ligases. We are focusing on the multi-subunit Cullin 5-RING ligase (CRL5), which interacts with pY
proteins through suppressors of cytokine signaling (SOCS) adaptor proteins. Our past studies have shown that
various CRL5-SOCS complexes are critical in normal epithelial cells to repress an oncogenic PTK, Src. When
we inhibit expression of Cullin 5 or specific SOCS genes, Src is activated and cell migration, proliferation and
transformation are stimulated. Increased Src activity is necessary but not sufficient for the migration and
proliferation of Cullin 5-deficient cells, suggesting that CRL5 has additional substrates. Our past studies have
identified two such substrates that are critical for cell migration. Here we propose to extend these studies, to
understand how CRL5-SOCS regulates epithelial cell migration. Our scientific premise is that the identification
of key CRL5-SOCS substrates and functions in migration is critical for understanding normal and transformed
cell biology.
During the last funding period, we used innovative live imaging, optogenetics and mutational analysis to
uncover the molecular mechanism by which CRL5-SOCS6 regulates the signaling scaffold, Cas (Crk-
associated substrate), within focal adhesion sites at the leading edge of migrating epithelial cells. We also used
quantitative proteomics to identify other CRL5 substrates and test their roles in cell migration. Specifically, we
identified BCAR3 (breast cancer anti-estrogen resistance 3) as a second CRL5-SOCS6 substrate that
regulates cell migration. Finally, we found that SOCS2, like SOCS6, localizes to focal adhesion sites and
regulates cytoskeletal dynamics.
We propose three broad aims to extend these observations and understand the molecular mechanisms. First,
we will understand the importance of BCAR3 phosphorylation in BCAR3 stability and focal adhesion dynamics.
Second, BCAR3 binds and cooperates with Cas: each protein stabilizes the other from degradation. We will
understand the mechanism and importance of BCAR3-Cas mutual stabilization. Third, we will determine the
mechanism by which SOCS2 regulates focal adhesion dynamics. Together, these aims will extend our
understanding of how protein-tyrosine phosphorylation and ubiquitylation cooperate to regulate cell migration.

## Key facts

- **NIH application ID:** 10064153
- **Project number:** 5R01GM109463-07
- **Recipient organization:** FRED HUTCHINSON CANCER RESEARCH CENTER
- **Principal Investigator:** Jonathan A Cooper
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $369,600
- **Award type:** 5
- **Project period:** 2014-08-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10064153

## Citation

> US National Institutes of Health, RePORTER application 10064153, Regulation of cell migration and signaling by phosphotyrosine and ubiquitin (5R01GM109463-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10064153. Licensed CC0.

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