Human kallikrein-related peptidase 14 (KLK14) is a new activator component of the KLK proteolytic cascade. Possible function in seminal plasma and skin.
Human kallikrein-related peptidases (KLKs) are a family of 15 serine proteases mainly known for their biomarker utility in various neoplastic and non-neoplastic diseases. Despite significant progress in understanding their clinical application, little is known about the activation mechanism(s) of this important family of enzymes. Emerging evidence indicates that KLKs are activated in a stepwise manner, which is a characteristic of proteolytic cascades. Thus far, KLK cascades have been implicated in semen liquefaction and skin desquamation. Many members of the KLK family have been reported to be active in seminal plasma and/or skin, suggesting their involvement in common proteolytic cascades. KLK14, in particular, is highly active and has recently been proposed as one of the key trypsin-like proteases involved in skin desquamation. This study aims to elucidate a probable cascade-mediated role of KLK14 by 1) examining KLK14-mediated cleavage of a heptapeptide library encompassing activation sites of the 15 KLKs and 2) verifying activation of certain candidate downstream targets of KLK14 (i.e. pro-KLK1, -KLK3, and -KLK11). Heptapeptides encompassing activation motifs of KLK2, -3, -5, and -11 were cleaved with a high (> or =85%) cleavage efficiency. Activation of these candidates was confirmed using full-length recombinant proteins. Pro-KLK11, -KLK3, and -KLK1 were rapidly activated in a concentration-dependent manner. Pro-KLK3 regulation was bidirectional because activation was followed by inactivation via internal cleavage of active KLK3. We are proposing a putative cascade model, operating through multiple KLKs. Identification of novel members of such proteolytic cascades will aid in further defining mechanisms involved in seminal/skin homeostasis.
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5G-1L5, Canada and the Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada; Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.
Nashmil
N
Emami
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5G-1L5, Canada and the Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada; Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada. Electronic address: ediamandis@mtsinai.on.ca.
Eleftherios P
EP
Diamandis
D010450:Endopeptidases / Q000737:chemistry*; D005786:Gene Expression Regulation; D006801:Humans; D007610:Kallikreins / Q000737:chemistry* / Q000502:physiology*; D008297:Male; D019151:Peptide Library; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D011994:Recombinant Proteins / Q000737:chemistry; D012661:Semen / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000737:chemistry; D012867:Skin / Q000378:metabolism*; D013997:Time Factors; D014357:Trypsin / Q000737:chemistry
D019151:Peptide Library; D011994:Recombinant Proteins; D010450:Endopeptidases; C425336:KLK14 protein, human; D007610:Kallikreins; D012697:Serine Endopeptidases; D014357:Trypsin