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Prostate-specific membrane antigen regulates angiogenesis by modulating integrin signal transduction.
Rebecca E Conway1, Nenad Petrovic, Zhong Li
1University of Connecticut Health Center, Center for Vascular Biology MC3501, Department of Cell Biology, Farmington, CT 06030-350l, USA.
Molecular and Cellular Biology
|July 1, 2006
Summary
Prostate-specific membrane antigen (PSMA) plays a critical role in tumor angiogenesis by regulating endothelial cell invasion. PSMA functions in a novel feedback loop involving integrin signaling and PAK-1, impacting tumor growth.
Area of Science:
- Oncology
- Cell Biology
- Biochemistry
Background:
- Prostate-specific membrane antigen (PSMA) is upregulated in tumor vasculature.
- The role of PSMA in tumor angiogenesis remains largely uninvestigated.
Purpose of the Study:
- To elucidate the functional role of PSMA in tumor angiogenesis.
- To investigate the molecular mechanisms underlying PSMA's involvement in endothelial cell invasion and signaling pathways.
Main Methods:
- Utilized PSMA-null animal models to assess angiogenesis.
- Employed cell invasion assays, Western blotting, and protein interaction studies.
- Investigated the impact of PSMA inhibition, knockdown, and genetic deficiency on endothelial cell function.
Main Results:
- PSMA deficiency severely impairs angiogenesis due to defects in endothelial cell invasion.
- PSMA modulates laminin-specific integrin signaling and p21-activated kinase 1 (PAK-1) activity.
- PSMA functions within a negative feedback loop involving integrin beta(1) and PAK-1, regulated by cytoskeletal interactions with filamin A.
Conclusions:
- PSMA is a crucial regulator of tumor angiogenesis, acting as a molecular interface.
- PSMA integrates extracellular and intracellular signals to control endothelial cell invasion and signaling.
- Identified a novel autoregulatory loop involving PSMA, integrins, and PAK-1 that impacts tumor growth.