Projects and Grants per year
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Description
Recent approval of bortezomib, a drug that inhibits the 26S proteasome, has underscored the
importance of the ubiquitin proteasome pathway in cancer therapy. Protein ubiquitination has been
implicated in focal adhesion (FA) dynamics and cell migration, key steps in cancer metastasis.
However, the key ubiquitin pathways that govern this process remain to be identied. HECTD1 is a
280 kDa HECT domain E3 ubiquitin ligase essential for cell migration. Our preliminary data shows that
HECTD1 is highly expressed in breast cancer tissues and regulates FA dynamics. However, its
substrates, cellular functions and regulatory mechanisms remain to be elucidated.
Phosphatidylinositol 4 phosphate 5-kinase type I (PIPKI), an enzyme that produces
phosphatidylinositol 4,5-bisphosphate (PIP2), is essential for FA dynamics and cancer cell invasion.
PIPKIã and the integrin tail compete for the same binding site on talin, the activator of integrins.
In preliminary studies we found that depletion of HECTD1suppressed PIPKI ubiquitination leading to
our hypothesis that HECTD1-mediated PIPKI ubiquitination and subsequent degradation mediate FA
assembly/disassembly, cancer cell migration and metastasis by modulating talin- integrin interaction.
We will dene the role of PIPKI ubiquitination by HECTD1 in regulating FA dynamics, cell migration
and metastasis, determine how PIPKI ubiquitination regulate cell migration and metastasis, and
dissect how HECTD1 is regulated by Akt1 during cell migration and metastasis. Our ndings will
identify a novel pathway that accounts for a central mechanism for focal adhesion dynamics,
cell migration and metastasis, and will signicantly advance our understanding of the molecular
mechanisms of cancer cell migration and metastasis.
Status | Finished |
---|---|
Effective start/end date | 8/1/12 → 7/31/13 |
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Projects
- 1 Finished
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University of Kentucky Institutional Research Grant
Spear, B. (PI) & Davidson, J. (Former PI)
1/1/08 → 12/31/12
Project: Research project