Distinctly different gene structure of KLK4/KLK-L1/prostase/ARM1 compared with other members of the Kallikrein family: Intracellular localization, alternative cDNA forms, and regulation by multiple hormones

The tissue kallikreins (KLKs) form a family of serine proteases that are in volved in processing of polypeptide precursors and have important roles in a variety of physiologic and pathological processes. Common features of all tissue kallikrein genes identified to date in various species include a si milar genomic organization of five exons, a conserved triad of amino acids for serine protease catalytic activity, and a signal peptide sequence encod ed in the first exon. Here, we show that KLK4/KLK-L1/prostase/ARM1 (hereaft er called KLK4) is the first significantly divergent member of the kallikre in family. The exon predicted to code for a signal peptide is absent in KLK 4, which is likely to affect the function of the encoded protein. Green flu orescent protein (GFP)-tagged KLK4 has a distinct perinuclear localization, suggesting that its primary function is inside the cell, in contrast to th e other tissue kallikreins characterized so far that have major extracellul ar functions. There are at least two differentially spliced, truncated vari ants of KLK4 that are either exclusively or predominantly localized to the nucleus when labeled with GFP. Furthermore, KLK4 expression is regulated by multiple hormones in prostate cancer cells and is deregulated in the andro gen-independent phase of prostate cancer. These findings demonstrate that K LK4 is a unique member of the kallikrein family that may have a role in the progression of prostate cancer.