Human tissue kallikrein 5 is a member of a proteolytic cascade pathway involved in seminal clot liquefaction and potentially in prostate cancer progression.
Human tissue kallikreins (hKs) are a family of fifteen serine proteases. Several lines of evidence suggest that hKs participate in proteolytic cascade pathways. Human kallikrein 5 (hK5) has trypsin-like activity, is able to self-activate, and is co-expressed in various tissues with other hKs. In this study, we examined the ability of hK5 to activate other hKs. By using synthetic heptapeptides that encompass the activation site of each kallikrein and recombinant pro-hKs, we demonstrated that hK5 is able to activate pro-hK2 and pro-hK3. We then showed that, following their activation, hK5 can internally cleave and deactivate hK2 and hK3. Given the predominant expression of hK2 and hK3 in the prostate, we examined the pathophysiological role of hK5 in this tissue. We studied the regulation of hK5 activity by cations (Zn2+, Ca2+, Mg2+, Na2+, and K+) and citrate and showed that Zn can efficiently inhibit hK5 activity at levels well below its normal concentration in the prostate. We also show that hK5 can degrade semenogelins I and II, the major components of the seminal clot. Semenogelins can reverse the inhibition of hK5 by Zn2+, providing a novel regulatory mechanism of its serine protease activity. hK5 is also able to internally cleave insulin-like growth factor-binding proteins 1, 2, 3, 4, and 5, but not 6, suggesting that it might be involved in prostate cancer progression through growth factor regulation. Our results uncover a kallikrein proteolytic cascade pathway in the prostate that participates in seminal clot liquefaction and probably in prostate cancer progression.
Michael
Iacovos P
IP
Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.
Pampalakis
Georgios
G
Mikolajczyk
Stephen D
SD
Malm
Johan
J
Sotiropoulou
Georgia
G
Diamandis
Eleftherios P
EP
D001777:Blood Coagulation; D002412:Cations; D018450:Disease Progression; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000378:metabolism; D007477:Ions; D007610:Kallikreins / Q000737:chemistry / Q000502:physiology*; D008297:Male; D008954:Models, Biological; D010455:Peptides / Q000737:chemistry; D011471:Prostatic Neoplasms / Q000473:pathology*; D011994:Recombinant Proteins / Q000737:chemistry; D014357:Trypsin / Q000737:chemistry; D015032:Zinc / Q000737:chemistry
D002412:Cations; D018969:Insulin-Like Growth Factor Binding Proteins; D007477:Ions; D010455:Peptides; D011994:Recombinant Proteins; C400147:KLK5 protein, human; D007610:Kallikreins; D014357:Trypsin; D015032:Zinc