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Molecular and Cellular Biology, July 2006, p. 5310-5324, Vol. 26, No. 14
0270-7306/06/$08.00+0     doi:10.1128/MCB.00084-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Prostate-Specific Membrane Antigen Regulates Angiogenesis by Modulating Integrin Signal Transduction{dagger}

Rebecca E. Conway,1 Nenad Petrovic,1 Zhong Li,2 Warren Heston,3 Dianqing Wu,2 and Linda H. Shapiro1*

Departments of Cell Biology,1 Genetics and Developmental Biology, University of Connecticut Health Center, Farmington, Connecticut 06030,2 Department of Cancer Biology and Urological Institute, Cleveland Clinic Foundation, Cleveland, Ohio 441953

Received 13 January 2006/ Returned for modification 20 February 2006/ Accepted 1 May 2006

The transmembrane peptidase prostate-specific membrane antigen (PSMA) is universally upregulated in the vasculature of solid tumors, but its functional role in tumor angiogenesis has not been investigated. Here we show that angiogenesis is severely impaired in PSMA-null animals and that this angiogenic defect occurs at the level of endothelial cell invasion through the extracellular matrix barrier. Because proteolytic degradation of the extracellular matrix is a critical component of endothelial invasion in angiogenesis, it is logical to assume that PSMA participates in matrix degradation. However, we demonstrate a novel and more complex role for PSMA in angiogenesis, where it is a principal component of a regulatory loop that is tightly modulating laminin-specific integrin signaling and GTPase-dependent, p21-activated kinase 1 (PAK-1) activity. We show that PSMA inhibition, knockdown, or deficiency decreases endothelial cell invasion in vitro via integrin and PAK, thus abrogating angiogenesis. Interestingly, the neutralization of ß1 or the inactivation of PAK increases PSMA activity, suggesting that they negatively regulate PSMA. This negative regulation is mediated by the cytoskeleton as the disruption of interactions between the PSMA cytoplasmic tail and the anchor protein filamin A decreases PSMA activity, integrin function, and PAK activation. Finally, the inhibition of PAK activation enhances the PSMA/filamin A interaction and, thus, boosts PSMA activity. These data imply that PSMA participates in an autoregulatory loop, wherein active PSMA facilitates integrin signaling and PAK activation, leading to both productive invasion and downregulation of integrin ß1 signaling via reduced PSMA activity. Therefore, we have identified a novel role for PSMA as a true molecular interface, integrating both extracellular and intracellular signals during angiogenesis.

* Corresponding author. Mailing address: University of Connecticut Health Center, Center for Vascular Biology MC3501, Department of Cell Biology, Farmington, CT 06030-350l. Phone: (860) 679-4373. Fax: (860) 679-1201. E-mail: lshapiro{at}neuron.uchc.edu.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, July 2006, p. 5310-5324, Vol. 26, No. 14
0270-7306/06/$08.00+0     doi:10.1128/MCB.00084-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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