Cathepsin H Mediates the Processing of Talin and Regulates Migration of Prostate Cancer Cells

• Published in: The Journal of biological chemistry 2013-01, Vol.288 (4), p.2201-2209
• Main Authors: Jevnikar, Zala, Rojnik, Matija, Jamnik, Polona, Doljak, Bojan, Fonović, Urša Pečar, Kos, Janko
• Format: Article
• Language: English
• Subjects: Aminopeptidases - chemistry; Cathepsin H - metabolism; Cell Biology; Cell Line, Tumor; Cell Migration; Cell Movement; Cell Separation; Cysteine Protease; Electrophoresis, Gel, Two-Dimensional - methods; Enzyme-Linked Immunosorbent Assay - methods; Flow Cytometry; Gene Expression Regulation, Neoplastic; Humans; Integrin alphaVbeta3 - metabolism; Integrins; Integrins - metabolism; Male; Microscopy, Fluorescence - methods; Molecular Cell Biology; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; RNA, Small Interfering - metabolism; Talin - metabolism; Tumor Cell Biology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M112.436394

The cytoskeletal protein talin, an actin- and β-integrin tail-binding protein, plays an important role in cell migration by promoting integrin activation and focal adhesion formation. Here, we show that talin is a substrate for cathepsin H (CtsH), a lysosomal cysteine protease with a strong aminopeptidase activity. Purified active CtsH sequentially cleaved a synthetic peptide representing the N terminus of the talin F0 head domain. The processing of talin by CtsH was determined also in the metastatic PC-3 prostate cancer cell line, which exhibits increased expression of CtsH. The attenuation of CtsH aminopeptidase activity by a specific inhibitor or siRNA-mediated silencing significantly reduced the migration of PC-3 cells on fibronectin and invasion through Matrigel. We found that in migrating PC-3 cells, CtsH was co-localized with talin in the focal adhesions. Furthermore, specific inhibition of CtsH increased the activation of αvβ3-integrin on PC-3 cells. We propose that CtsH-mediated processing of talin might promote cancer cell progression by affecting integrin activation and adhesion strength. Background: Cathepsin H (CtsH) is an aminopeptidase that is involved in tumor progression. Results: CtsH cleaves talin, and its inhibition reduces the migration of prostate cancer cells. Conclusion: CtsH affects cell migration by influencing the activity of integrins, a process that could be regulated by talin cleavage. Significance: Identification of novel CtsH proteolytic targets is important to understand and control tumor progression.