This Article Full Text Full Text (PDF) Supplemental material Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Conway, R. E. Articles by Shapiro, L. H. Search for Related Content PubMed PubMed Citation Articles by Conway, R. E. Articles by Shapiro, L. H.

 Previous Article  |  Next Article 

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

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.

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

This article has been cited by other articles:

• Terrier, B., Tamby, M. C., Camoin, L., Guilpain, P., Broussard, C., Bussone, G., Yaici, A., Hotellier, F., Simonneau, G., Guillevin, L., Humbert, M., Mouthon, L. (2008). Identification of Target Antigens of Antifibroblast Antibodies in Pulmonary Arterial Hypertension. Am. J. Respir. Crit. Care Med. 177: 1128-1134 [Abstract] [Full Text]  
• Morris, M. J., Pandit-Taskar, N., Divgi, C. R., Bender, S., O'Donoghue, J. A., Nacca, A., Smith-Jones, P., Schwartz, L., Slovin, S., Finn, R., Larson, S., Scher, H. I. (2007). Phase I Evaluation of J591 as a Vascular Targeting Agent in Progressive Solid Tumors. Clin. Cancer Res. 13: 2707-2713 [Abstract] [Full Text]