Abstract
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 α(v)β(3)-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.
Highlights
Cathepsin H (CtsH) is an aminopeptidase that is involved in tumor progression
The results clearly show the N-terminal sequential cleavage of the synthetic peptide, indicating that CtsH processes the N-terminal region of talin primarily by its monoaminopeptidase activity
A previous report showed that CtsH is not able to hydrolyze substrates by its aminopeptidase activity if proline is present at the S1Ј position [19]
Summary
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. We propose that CtsH-mediated processing of talin might promote cancer cell progression by affecting integrin activation and adhesion strength. The other subdomains are not directly involved in integrin binding, they cooperate with talin F3 to mediate integrin activation by targeting talin to integrins [11] and by interaction with the adjacent phospholipids of the plasma membrane [9, 12, 13] Because of their involvement in cell migration, integrincontaining adhesion complexes are dynamic structures that undergo repeated cycles of formation and disassembly [14]. Cathepsin H-dependent Processing of Talin study, we identify a CtsH as a new cysteine protease capable of proteolytic cleavage of talin It cleaves sequentially the N terminus of the talin F0 head domain by its monoaminopeptidase activity. We show that CtsH co-localizes with talin at FAs, where it modulates the activation of ␣v3-integrins
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