This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Afar, D. E. H. Articles by Jakobovits, A. Search for Related Content PubMed PubMed Citation Articles by Afar, D. E. H. Articles by Jakobovits, A.

Catalytic Cleavage of the Androgen-regulated TMPRSS2 Protease Results in Its Secretion by Prostate and Prostate Cancer Epithelia

UroGenesys Inc., Santa Monica, California 90404

We identified TMPRSS2 as a gene that is down-regulated in androgen-independent prostate cancer xenograft tissue derived from a bone metastasis. Using specific monoclonal antibodies, we show that the TMPRSS2-encoded serine protease is expressed as a M_r 70,000 full-length form and a cleaved M_r 32,000 protease domain. Mutation of Ser-441 in the catalytic triad shows that the proteolytic cleavage is dependent on catalytic activity, suggesting that it occurs as a result of autocleavage. Mutational analysis reveals the cleavage site to be at Arg-255. A consequence of autocatalytic cleavage is the secretion of the protease domain into the media by TMPRSS2-expressing prostate cancer cells and into the sera of prostate tumor-bearing mice. Immunohistochemical analysis of clinical specimens demonstrates the highest expression of TMPRSS2 at the apical side of prostate and prostate cancer secretory epithelia and within the lumen of the glands. Similar luminal staining was detected in colon cancer samples. Expression was also seen in colon and pancreas, with little to no expression detected in seven additional normal tissues. These data demonstrate that TMPRSS2 is a secreted protease that is highly expressed in prostate and prostate cancer, making it a potential target for cancer therapy and diagnosis.

This article has been cited by other articles:

				T. H. Bugge, T. M. Antalis, and Q. Wu Type II Transmembrane Serine Proteases J. Biol. Chem., August 28, 2009; 284(35): 23177 - 23181. [Abstract] [Full Text] [PDF]

				A. J. Ramsay, J. D. Hooper, A. R. Folgueras, G. Velasco, and C. Lopez-Otin Matriptase-2 (TMPRSS6): a proteolytic regulator of iron homeostasis Haematologica, June 1, 2009; 94(6): 840 - 849. [Abstract] [Full Text] [PDF]

				Y. Shirogane, M. Takeda, M. Iwasaki, N. Ishiguro, H. Takeuchi, Y. Nakatsu, M. Tahara, H. Kikuta, and Y. Yanagi Efficient Multiplication of Human Metapneumovirus in Vero Cells Expressing the Transmembrane Serine Protease TMPRSS2 J. Virol., September 1, 2008; 82(17): 8942 - 8946. [Abstract] [Full Text] [PDF]

				A. J. Ramsay, Y. Dong, M. L. Hunt, M. Linn, H. Samaratunga, J. A. Clements, and J. D. Hooper Kallikrein-related Peptidase 4 (KLK4) Initiates Intracellular Signaling via Protease-activated Receptors (PARs): KLK4 AND PAR-2 ARE CO-EXPRESSED DURING PROSTATE CANCER PROGRESSION J. Biol. Chem., May 2, 2008; 283(18): 12293 - 12304. [Abstract] [Full Text] [PDF]

				E. Bottcher, T. Matrosovich, M. Beyerle, H.-D. Klenk, W. Garten, and M. Matrosovich Proteolytic Activation of Influenza Viruses by Serine Proteases TMPRSS2 and HAT from Human Airway Epithelium J. Virol., October 1, 2006; 80(19): 9896 - 9898. [Abstract] [Full Text] [PDF]

				K.-i. Kiyomiya, M.-S. Lee, I-C. Tseng, H. Zuo, R. J. Barndt, M. D. Johnson, R. B. Dickson, and C.-Y. Lin Matriptase activation and shedding with HAI-1 is induced by steroid sex hormones in human prostate cancer cells, but not in breast cancer cells Am J Physiol Cell Physiol, July 1, 2006; 291(1): C40 - C49. [Abstract] [Full Text] [PDF]

				S. A. Tomlins, R. Mehra, D. R. Rhodes, L. R. Smith, D. Roulston, B. E. Helgeson, X. Cao, J. T. Wei, M. A. Rubin, R. B. Shah, et al. TMPRSS2:ETV4 gene fusions define a third molecular subtype of prostate cancer. Cancer Res., April 1, 2006; 66(7): 3396 - 3400. [Abstract] [Full Text] [PDF]

				T. S. Kim, C. Heinlein, R. C. Hackman, and P. S. Nelson Phenotypic Analysis of Mice Lacking the Tmprss2-Encoded Protease Mol. Cell. Biol., February 1, 2006; 26(3): 965 - 975. [Abstract] [Full Text] [PDF]

				L.-Y. Luo, S. J.C. Shan, M. B. Elliott, A. Soosaipillai, and E. P. Diamandis Purification and Characterization of Human Kallikrein 11, a Candidate Prostate and Ovarian Cancer Biomarker, from Seminal Plasma Clin. Cancer Res., February 1, 2006; 12(3): 742 - 750. [Abstract] [Full Text] [PDF]

				S. A. Tomlins, D. R. Rhodes, S. Perner, S. M. Dhanasekaran, R. Mehra, X.-W. Sun, S. Varambally, X. Cao, J. Tchinda, R. Kuefer, et al. Recurrent Fusion of TMPRSS2 and ETS Transcription Factor Genes in Prostate Cancer Science, October 28, 2005; 310(5748): 644 - 648. [Abstract] [Full Text] [PDF]

				Y. Zhang, X.-W. Wang, D. Jelovac, T. Nakanishi, M.-h. Yu, D. Akinmade, O. Goloubeva, D. D. Ross, A. Brodie, and A. W. Hamburger The ErbB3-binding protein Ebp1 suppresses androgen receptor-mediated gene transcription and tumorigenesis of prostate cancer cells PNAS, July 12, 2005; 102(28): 9890 - 9895. [Abstract] [Full Text] [PDF]

				A Noel, C Maillard, N Rocks, M Jost, V Chabottaux, N E Sounni, E Maquoi, D Cataldo, and J M Foidart Membrane associated proteases and their inhibitors in tumour angiogenesis J. Clin. Pathol., June 1, 2004; 57(6): 577 - 584. [Abstract] [Full Text] [PDF]

				S. Cal, V. Quesada, C. Garabaya, and C. Lopez-Otin Polyserase-I, a human polyprotease with the ability to generate independent serine protease domains from a single translation product PNAS, August 5, 2003; 100(16): 9185 - 9190. [Abstract] [Full Text] [PDF]

				G. Velasco, S. Cal, V. Quesada, L. M. Sanchez, and C. Lopez-Otin Matriptase-2, a Membrane-bound Mosaic Serine Proteinase Predominantly Expressed in Human Liver and Showing Degrading Activity against Extracellular Matrix Proteins J. Biol. Chem., September 27, 2002; 277(40): 37637 - 37646. [Abstract] [Full Text] [PDF]