Matriptase/pdgf D/beta-Pdgfr Signaling Axis In Human Prostate Cancer: The Role Of Pten In The Regulation Of Pdgf D Expression

<p>Platelet Derived Growth Factor (PDGF) is a family of mesenchymal growth factors that regulate cell proliferation, migration, and differentiation. Unlike the classic PDGF ligands A and B, which are secreted as active dimers, PDGF D must undergo extracellular proteolytic processing to remove its N-terminal CUB domain from the C-terminal PDGF growth domain before the ligand is able to stimulate its receptor, PDGF receptor beta (?-PDGFR). Importantly, recent clinical studies have shown that ?-PDGFR is upregulated in primary prostate cancer and bone metastases. However, PDGF B, formerly thought to be the sole ligand for ?-PDGFR, is not expressed in clinical prostate cancer samples. In a study of human primary prostate carcinoma and bone metastases, we found that PDGF D and matriptase are associated with prostate cancer progression. Additionally, in a clinically relevant prostate-specific PTEN (phosphatase and tensin homolog) knockout mouse model, we found an increase in PDGF D expression and ?-PDGFR phosphorylation upon loss of PTEN. Upon inhibition of the PI3K pathway, PDGF D/ ?-PDGFR induction was abolished in PTEN-/- cells. Among Akt isoforms, downstream effectors of PI3K, increased Akt3 expression was most prominent in PTEN-/- cells. These results suggest a molecular basis for activation of PDGF D/?-PDGFR signaling driven by the loss of PTEN, a frequent occurrence in human prostate cancer. Similarly, PTEN/Akt3 expression correlates with PDGF expression in human PCa cell lines, DU145 and PC3. Taken together, these results suggest that loss of PTEN in prostate cancer results in upregulation of PDGF D, which can then be activated by increased levels of serine proteases. The active growth domain is then able to activate ?-PDGFR, thus causing subsequent downstream signaling.</p>

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Open Access Dissertation

Discipline thesis:degree_discipline

Cancer Biology

Year dc:date.available

2010

Author dc:creator

• Conley-Lacomb, M. Katie

Contributors dc:contributor

• Hyeong-Reh C. Kim

• Growth Factors
• Matriptase
• PDGF D
• Protease
• PTEN
• Cell Biology

Repository record dc:identifier

https://digitalcommons.wayne.edu/oa_dissertations/58

OAI identifier oai:identifier

oai:digitalcommons.wayne.edu:oa_dissertations-1057