Tags

Type your tag names separated by a space and hit enter

Laminin-332 is a substrate for hepsin, a protease associated with prostate cancer progression.
J Biol Chem 2008; 283(45):30576-84JB

Abstract

Hepsin, a cell surface protease, is widely reported to be overexpressed in more than 90% of human prostate tumors. Hepsin expression correlates with tumor progression, making it a significant marker and target for prostate cancer. Recently, it was reported that in a prostate cancer mouse model, hepsin up-regulation in tumor tissue promotes progression and metastasis. The underlying mechanisms, however, remain largely uncharacterized. Hepsin transgenic mice displayed reduced laminin-332 (Ln-332) expression in prostate tumors. This is an intriguing cue, since proteolytic processing of extracellular matrix macromolecules, such as Ln-332, is believed to be involved in cancer progression, and Ln-332 expression is lost during human prostate cancer progression. In this study, we provide the first direct evidence that hepsin cleaves Ln-332. Cleavage is specific, since it is both inhibited in a dose-dependent manner by a hepsin inhibitor (Kunitz domain-1) and does not occur when catalytically inactive hepsin is used. By Western blotting and mass spectrometry, we determined that hepsin cleaves the beta3 chain of Ln-332. N-terminal sequencing identified the cleavage site at beta3 Arg(245), in a sequence context (SQLR(245) LQGSCFC) conserved among species and in remarkable agreement with reported consensus target sequences for hepsin activity. In vitro cell migration assays showed that hepsin-cleaved Ln-332 enhanced motility of DU145 prostate cancer cells, which was inhibited by Kunitz domain-1. Further, hepsin-overexpressing LNCaP prostate cancer cells also exhibited increased migration on Ln-332. Direct cleavage of Ln-332 may be one mechanism by which hepsin promotes prostate tumor progression and metastasis, possibly by up-regulating prostate cancer cell motility.

Authors+Show Affiliations

Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

18784072

Citation

Tripathi, Manisha, et al. "Laminin-332 Is a Substrate for Hepsin, a Protease Associated With Prostate Cancer Progression." The Journal of Biological Chemistry, vol. 283, no. 45, 2008, pp. 30576-84.
Tripathi M, Nandana S, Yamashita H, et al. Laminin-332 is a substrate for hepsin, a protease associated with prostate cancer progression. J Biol Chem. 2008;283(45):30576-84.
Tripathi, M., Nandana, S., Yamashita, H., Ganesan, R., Kirchhofer, D., & Quaranta, V. (2008). Laminin-332 is a substrate for hepsin, a protease associated with prostate cancer progression. The Journal of Biological Chemistry, 283(45), pp. 30576-84. doi:10.1074/jbc.M802312200.
Tripathi M, et al. Laminin-332 Is a Substrate for Hepsin, a Protease Associated With Prostate Cancer Progression. J Biol Chem. 2008 Nov 7;283(45):30576-84. PubMed PMID: 18784072.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Laminin-332 is a substrate for hepsin, a protease associated with prostate cancer progression. AU - Tripathi,Manisha, AU - Nandana,Srinivas, AU - Yamashita,Hironobu, AU - Ganesan,Rajkumar, AU - Kirchhofer,Daniel, AU - Quaranta,Vito, Y1 - 2008/09/09/ PY - 2008/9/12/pubmed PY - 2008/12/24/medline PY - 2008/9/12/entrez SP - 30576 EP - 84 JF - The Journal of biological chemistry JO - J. Biol. Chem. VL - 283 IS - 45 N2 - Hepsin, a cell surface protease, is widely reported to be overexpressed in more than 90% of human prostate tumors. Hepsin expression correlates with tumor progression, making it a significant marker and target for prostate cancer. Recently, it was reported that in a prostate cancer mouse model, hepsin up-regulation in tumor tissue promotes progression and metastasis. The underlying mechanisms, however, remain largely uncharacterized. Hepsin transgenic mice displayed reduced laminin-332 (Ln-332) expression in prostate tumors. This is an intriguing cue, since proteolytic processing of extracellular matrix macromolecules, such as Ln-332, is believed to be involved in cancer progression, and Ln-332 expression is lost during human prostate cancer progression. In this study, we provide the first direct evidence that hepsin cleaves Ln-332. Cleavage is specific, since it is both inhibited in a dose-dependent manner by a hepsin inhibitor (Kunitz domain-1) and does not occur when catalytically inactive hepsin is used. By Western blotting and mass spectrometry, we determined that hepsin cleaves the beta3 chain of Ln-332. N-terminal sequencing identified the cleavage site at beta3 Arg(245), in a sequence context (SQLR(245) LQGSCFC) conserved among species and in remarkable agreement with reported consensus target sequences for hepsin activity. In vitro cell migration assays showed that hepsin-cleaved Ln-332 enhanced motility of DU145 prostate cancer cells, which was inhibited by Kunitz domain-1. Further, hepsin-overexpressing LNCaP prostate cancer cells also exhibited increased migration on Ln-332. Direct cleavage of Ln-332 may be one mechanism by which hepsin promotes prostate tumor progression and metastasis, possibly by up-regulating prostate cancer cell motility. SN - 0021-9258 UR - https://www.unboundmedicine.com/medline/citation/18784072/Laminin_332_is_a_substrate_for_hepsin_a_protease_associated_with_prostate_cancer_progression_ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=18784072 DB - PRIME DP - Unbound Medicine ER -