Cell migration is regulated by signals from cell-cell interactions, cell-matrix interactions and chemo-attractants and -repellants. Such signals are transduced and coordinated by cascades of post-translational modifications and protein-protein interactions. Specifically, Src family tyrosine kinases are activated by mitogens and adhesion receptors and phosphorylate proteins that organize the leading edge and focal adhesions in migrating cells. The Cullin 5 RING (CRL5) E3 ubiquitin ligase and SOCS proteins (phosphotyrosine-dependent substrate adaptors for CRL5) have been implicated as potential tumor suppressors. We have found that SOCS-CRL5 complexes regulate Src activity, cell migration, proliferation and/or transformation in several cell types. Inhibiting the expression of SOCS proteins or Cul5 in epithelial cells stimulates migration, proliferation, and Src kinase activity. Increased Src is necessary but not sufficient for the increased migration and proliferation of CRL5-deficient cells, suggesting that SOCS-CRL5 complexes have additional substrates. We propose three broad aims to understand in depth how CRL5 regulates Src and cell migration. First, we will determine how CRL5 regulates Src activity. Second, we will identify CRL5 substrates, focusing on those that contain phosphotyrosine, and test which substrates regulate cell migration and proliferation. Third, we will dissect the mechanisms by which SOCS proteins and substrates coordinate focal adhesion and leading edge dynamics during cell migration. Collectively, our research will show how protein-tyrosine phosphorylation and ubiquitylation cooperate to regulate cell biology.

Public Health Relevance

The proposed research will investigate the molecular links between two forms of protein modification - phosphorylation and ubiquitylation - and how they regulate signaling and cell migration. The results may be relevant for understanding changes in signaling and cell migration in wound healing, immunity and cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM109463-01A1
Application #
8760249
Study Section
Intercellular Interactions (ICI)
Program Officer
Nie, Zhongzhen
Project Start
2014-08-01
Project End
2018-05-31
Budget Start
2014-08-01
Budget End
2015-05-31
Support Year
1
Fiscal Year
2014
Total Cost
$346,014
Indirect Cost
$149,415
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109