KLK3

KLK3 Full Name

kallikrein-related peptidase 3

KLK3 Introduction

Kallikrein-related peptidase 3 (KLK3), widely known as prostate-specific antigen (PSA), is a member of the kallikrein family of serine proteases encoded by the KLK3 gene located on human chromosome 19q13.33. This gene produces a single-chain glycoprotein that is synthesized primarily in the epithelial cells of the prostate gland and secreted into seminal fluid, where it plays a key physiological role in liquefying the seminal coagulum by hydrolyzing proteins such as semenogelin-1 to facilitate sperm motility. Alternate splicing of KLK3 generates multiple transcript variants, but all encode proteases closely related in structure and function. Although PSA expression is largely prostate-specific, low levels of KLK3/PSA may also be detected in other tissues such as female paraurethral glands, and its enzymatic activity is regulated by androgen receptor signaling and other local factors in the reproductive tract.

Figure 1.Signaling cascade of kallikrein 3 (KLK3) activation during liquefaction process.(Sources: Anamthathmakula P, et al.; 2020)

Beyond its normal physiological role, KLK3 has important biological activities that may influence tissue microenvironments and disease processes. As an active serine protease, PSA can interact with other proteins and growth factors, potentially influencing processes such as extracellular matrix remodeling or angiogenesis; some studies suggest it may have both anti-angiogenic and pro-angiogenic effects depending on context and substrate interactions, including effects on VEGF-C/D processing. The proteolytic activity of KLK3 also extends to insulin-like growth factor-binding proteins, which can alter levels of free IGF-1 and affect cellular growth signaling. Hence, KLK3 is not merely a passive biomarker but may participate in pathways relevant to cancer biology and cell signaling.

Clinically, KLK3/PSA is most widely known as a biomarker for prostate health, especially in the screening, diagnosis, and monitoring of prostate cancer (PCa). Elevated serum PSA levels are often observed in PCa, though increases may also result from benign prostatic hyperplasia or prostatitis, and low-activity variants can produce false-negative results if gene function is impaired. Genetic variation in the KLK3 locus influences circulating PSA concentrations and has been linked to differences in prostate cancer susceptibility and detection, because some single-nucleotide polymorphisms modulate PSA expression or androgen receptor response. While PSA screening has been essential for early PCa detection, interpretation requires caution due to these confounding factors and the influence of age, prostate size, and other conditions on PSA levels. Beyond prostate cancer, emerging genome-wide association studies have even suggested potential associations of KLK3 variants with other conditions, such as dermatophytosis susceptibility, highlighting the broader complexity of kallikrein biology in human disease.

Alternate Names for KLK3

KLK3; kallikrein-related peptidase 3; APS; PSA; hK3; KLK2A1; prostate-specific antigen; seminin; P-30 antigen; kallikrein-3; semenogelase; gamma-seminoprotein; prostate specific antigen;

• 1. Anamthathmakula P, Winuthayanon W. Mechanism of semen liquefaction and its potential for a novel non-hormonal contraception?. Biol Reprod. 2020, 103(2):411-426.