Kallikrein-related peptidases constitute a single family of 15 (chymo)trypsin-like proteases (KLK1–15) with pleiotropic physiological roles. Aberrant regulation of KLKs has been associated with diverse diseases such as hypertension, renal dysfunction, skin disorders, inflammation, neurodegeneration, and cancer. Recent studies suggested that coordinated activation and regulation of KLK activity are achieved via a complex network of interactions referred to as the "KLK activome." However, it remains to be validated whether these hypothetical KLK activation cascade pathways are operative in vivo. In addition, KLKs have emerged as versatile signaling molecules. In summary, KLKs represent attractive biomarkers for clinical applications and potential therapeutic targets for common human pathologies.

Transformation of normal cells into malignant tumors requires the acquisition of six hallmark traits, e.g., self-sufficiency in growth signals, insensitivity to antigrowth signals and self-renewal, evasion of apoptosis, limitless replication potential, angiogenesis, invasion, and metastasis, which are common to all cancers (Hanahan and Weinberg 2000). These new cellular traits evolve from defects in major regulatory microcircuits that are fundamental for normal homeostasis. The discovery of microRNAs (miRNAs) as a new class of small non-protein-coding RNAs that control gene expression post-transcriptionally by binding to various mRNA targets suggests that these tiny RNA molecules likely act as molecular switches in the extensive regulatory web that involves thousands of transcripts. Most importantly, accumulating evidence suggests that numerous microRNAs are aberrantly expressed in human cancers. In this review, we discuss the emergent roles of microRNAs as switches that function to turn on/off known cellular microcircuits. We outline recent compelling evidence that deregulated microRNA-mediated control of cellular microcircuits cooperates with other well-established regulatory mechanisms to confer the hallmark traits of the cancer cell. Furthermore, these exciting insights into aberrant microRNA control in cancer-associated circuits may be exploited for cancer therapies that will target deregulated miRNA switches.

Netherton Syndrome (NS) is a rare and severe autosomal recessive skin disease which can be life-threatening in infants. The disease is characterized by extensive skin desquamation, inflammation, allergic manifestations and hair shaft defects. NS is caused by loss-of-function mutations in SPINK5 encoding the LEKTI serine protease inhibitor. LEKTI deficiency results in unopposed activities of kallikrein-related peptidases (KLKs) and aberrantly increased proteolysis in the epidermis. Spink5^-/- mice recapitulate the NS phenotype, display enhanced epidermal Klk5 and Klk7 protease activities and die within a few hours after birth because of a severe skin barrier defect. However the contribution of these various proteases in the physiopathology remains to be determined. In this study, we developed a new murine model in which Klk5 and Spink5 were both knocked out to assess whether Klk5 deletion is sufficient to reverse the NS phenotype in Spink5^-/- mice. By repeated intercrossing between Klk5^-/- mice with Spink5^-/- mice, we generated Spink5^-/-Klk5^-/- animals. We showed that Klk5 knock-out in Lekti-deficient newborn mice rescues neonatal lethality, reverses the severe skin barrier defect, restores epidermal structure and prevents skin inflammation. Specifically, using in situ zymography and specific protease substrates, we showed that Klk5 knockout reduced epidermal proteolytic activity, particularly its downstream targets proteases KLK7, KLK14 and ELA2. By immunostaining, western blot, histology and electron microscopy analyses, we provide evidence that desmosomes and corneodesmosomes remain intact and that epidermal differentiation is restored in Spink5^-/-Klk5^-/-. Quantitative RT-PCR analyses and immunostainings revealed absence of inflammation and allergy in Spink5^-/-Klk5^-/- skin. Notably, Il-1β, Il17A and Tslp levels were normalized. Our results provide in vivo evidence that KLK5 knockout is sufficient to reverse NS-like symptoms manifested in Spink5^-/- skin. These findings illustrate the crucial role of protease regulation in skin homeostasis and inflammation, and establish KLK5 inhibition as a major therapeutic target for NS. Netherton Syndrome (NS) is a severe form of ichthyosis characterized by desquamation, inflammation and multiple allergies, which can be life-threatening in infants. NS is caused by loss-of-function mutations in SPINK5 encoding the LEKTI serine protease inhibitor. Current treatment options for this orphan disease are non-curative, focusing on the management of skin infections and the reduction of itching and pain. We developed a new murine model in which Klk5 and Spink5 were both inactivated to assess whether Klk5 loss is sufficient to reverse the NS phenotype in Spink5^-/- mice. Here, we identified Klk5 as the major determinant of NS pathology. Solely by deleting Klk5 gene, we successfully demonstrated reversal of both desquamating and inflammatory manifestations of NS. These were accompanied by drastic improvement of skin barrier defect, restoration of normal epidermal differentiation and epidermal ultrastructure. Our data identified KLK5 as a new target for drug development in NS, thus setting the foundation for designing the first targeted therapy against NS. NS shares several biological features and proteolytic unbalance with other inflammatory skin diseases such as atopic dermatitis, rosacea, and psoriasis. An increasing population suffers from these frequent skin diseases. Our findings could therefore have implication in the treatment of these common and disabling diseases.

Kallikrein-related peptidases (KLKs) constitute a family of 15 highly conserved serine proteases encoded by the largest uninterrupted cluster of protease-encoding genes within the human genome. Recent studies, mostly relying onin vitroproteolysis of recombinant proteins, have suggested that KLK activities are regulated by proteolytic activation cascades that can operate in a tissue-specific manner, such as the semen liquefaction and skin desquamation cascades. The validity of KLK activation cascadesin vivolargely remains to be demonstrated. Here, we focus on recent investigations showing that KLKs represent interesting players in the broader field of immunology based on their ability to bridge their inherent ability to degrade the extracellular matrix with major functions of the immune system. More specifically, KLKs assist in the infiltration of immune cells through the skin and the blood brain barrier, whereas they catalyze the generation of antimicrobial peptides by proteolytic activation and further processing of protein precursors. In an attempt to integrate current knowledge, we propose KLK-mediated pathways that are putatively involved in inflammation associated with skin wounding and central nervous system disorders, including multiple sclerosis. Finally, we present evidence of KLK participation in autoimmune diseases and allergies.

Netrin-1 overexpression is predictive of ovarian malignancies