Involvement of Kallikrein-Related Peptidases in Normal and Pathologic Processes

Abstract

Human kallikrein-related peptidases (KLKs) are a subgroup of serine proteases that participate in proteolytic pathways and control protein levels in normal physiology as well as in several pathological conditions. Their complex network of stimulatory and inhibitory interactions may induce inflammatory and immune responses and contribute to the neoplastic phenotype through the regulation of several cellular processes, such as proliferation, survival, migration, and invasion. This family of proteases, which includes one of the most useful cancer biomarkers, kallikrein-related peptidase 3 or PSA, also has a protective effect against cancer promoting apoptosis or counteracting angiogenesis and cell proliferation. Therefore, they represent attractive therapeutic targets and may have important applications in clinical oncology. Despite being intensively studied, many gaps in our knowledge on several molecular aspects of KLK functions still exist. This review aims to summarize recent data on their involvement in different processes related to health and disease, in particular those directly or indirectly linked to the neoplastic process.

Figure 1

KLK gene cluster and schematic representation of the human KLK gene and protein structure. (a) KLK gene cluster on the 19q13.33–13.41 chromosome region including the pseudogene KLKP1 and the transcriptional direction from centromere to telomere, except for KLK2 and KLK3, which have the opposite transcriptional direction. The classic KLK genes (KLKs 1–3) are turquoise, KLK4–KLK15 are medium purple, and the Ψ KLK1 processed pseudogene is silver; the arrowheads represent the neighboring genes: ACPT (testicular acid phosphatase) and the Siglec (sialic acid-binding immunoglobulin-like lectin) gene family as well as other less characterized genes (SNORDs, C19orf48, and CTU1). (b) The human KLK gene consists of 5 coding exons (orange boxes represent coding exons; silver boxes represent noncoding exons) and their 4 intervening introns. The positions of the catalytic residues are highly conserved with the histidine (H), aspartic acid (D) 3, and serine (S) codons on coding exons 2, 3, and 5, respectively. Most KLK genes demonstrate alternative splicing, which generates several transcript variants. Alternative 3′ splice sites or skipped exons (shown in green) result in short variants of KLKs 2, 3, 5, 8, and 12 genes. Alternative 5′ splice sites or start sites (shown in blue) also generate short variants of KLKs 2, 3, 6, 7, 8, and 11 genes. Utilization of the alternative exon 6 generates a long transcript encoding a variant of KLK12 gene (shown in blue). (c) KLK proteins are single-chain proteases that are synthesized as preproenzymes and are proteolytically processed to pro-KLKs and secreted after removal of the terminal signal peptide (Pre). The KLK sequence also includes a propeptide (Pro) that maintains the inactive state of the enzyme, as well as a serine protease domain.

Figure 2

Phylogenetic relationships within the human tissue KLK gene family in humans. Phylogenetic analysis was performed using the MEGA5 [205] and Maximum Likelihood methods based on the GTR model (General Time Reversible) [154] with Gamma distribution. The bootstrap method was used (with 1000 data set replicates) to investigate node robustness [206]. The phylogenetic tree includes 15 KLK transcripts, the pseudogene-1 (KLKP1) sequence, and the trypsin 1 gene sequence (PRSS1) [155, 156]. The sequences were obtained from the NCBI Reference Sequence (RefSeq) database (http://www.ncbi.nlm.nih.gov/). Numbers indicate the percentage of 1000 bootstrap replicates at each node in the consensus. Bootstrap value ≤95.

Figure 3

Schematic representation of KLK functions related to physiological and pathological conditions. KLKs are involved in several normal processes including blood pressure, coagulation, semen liquefaction, and skin desquamation and can also protect against cardiac injury and ischemia. These proteases may also participate in skin inflammation, neurodegeneration, and autoimmune diseases.

Figure 4

Kallikrein-related peptidases and cancer. KLKs participate in proteolytic pathways that contribute to the neoplastic process by facilitating cell proliferation via growth factors and modulating cell survival through mTOR signaling. They can also regulate angiogenesis, cell migration and invasion by angiogenic vascular endothelial growth factor (VEGF) secretion, metalloproteinase activation, extracellular matrix (ECM) degradation, and epithelial-mesenchymal transition (EMT) induction. However, KLKs also have a protective effect against cancer, promoting apoptosis or inhibiting angiogenesis and cell proliferation.