KLK2

KLK2 is a trypsin-like serine protease predominantly expressed in prostate luminal epithelium that functions as a key extracellular regulator of the prostatic microenvironment. KLK2 activates the PSA (KLK3) zymogen, as demonstrated across cell-based, xenograft, and transgenic mouse systems, establishing it as the physiological activator of PSA (PMID:20058238). KLK2 also degrades IGFBP-3 by cleaving after Arg residues, thereby modulating IGF bioavailability (PMID:20180640), and cleaves the extracellular domain of IL-10R2 on macrophages, impairing IL-10-mediated anti-inflammatory signaling and promoting prostatic inflammation (PMID:39106042). In prostate cancer cells, KLK2 cooperates with the AR coregulator ARA70 to enhance androgen receptor transactivation and promote cell growth, and a KLK2–FGFR2 gene fusion identified in metastatic prostate cancer constitutively activates FGFR signaling and is sensitive to FGFR inhibitors (PMID:24122203, PMID:31043681).

1. 2002 Medium

   Discovery of an alternative splice variant (K-LM) sharing only the signal peptide with KLK2 revealed unexpected transcript complexity at the KLK2 locus, raising the question of whether KLK2 gene products extend beyond the canonical serine protease.

   Evidence Molecular cloning and RT-PCR of KLK2 transcripts in prostate cells

   PMID:11834722

   Open questions at the time

   • No protein-level detection of K-LM or functional characterization reported
   • Physiological relevance of the splice variant remains undefined
2. 2008 Medium

   Development of specific peptide inhibitors of KLK2 confirmed that its trypsin-like catalytic activity could be selectively blocked, providing tools for downstream functional studies.

   Evidence Peptide-based enzymatic activity assays with cyclization chemistry for stability

   PMID:18627344

   Open questions at the time

   • Inhibitors tested only in vitro; no cellular or in vivo validation reported
   • Selectivity across the full kallikrein family not exhaustively profiled
3. 2010 High

   The long-standing question of which protease activates PSA zymogen in vivo was resolved by showing KLK2 is responsible, using multiple orthogonal systems including transgenic mice.

   Evidence Cell-based coincubation, xenograft co-inoculation, and prostate-targeted PSA/KLK2 double transgenic mouse models measuring free-to-total PSA ratio

   PMID:20058238

   Open questions at the time

   • Structural basis of KLK2–pro-PSA interaction not determined
   • Whether other proteases contribute redundantly to PSA activation in human prostate tissue in vivo
4. 2010 High

   Identification of IGFBP-3 as a KLK2 substrate expanded KLK2's role beyond PSA activation to extracellular matrix and growth factor signaling regulation.

   Evidence In vitro protease assay with immunoblotting, dual immunoassays, and mass spectrometry cleavage site mapping

   PMID:20180640

   Open questions at the time

   • IGFBP-3 cleavage by KLK2 not demonstrated in prostatic tissue or fluid
   • Downstream effects on IGF-I bioavailability not measured
5. 2014 Medium

   A nuclear/transcriptional role for KLK2 was suggested by its cooperation with ARA70 to enhance AR transactivation and its requirement for prostate cancer cell proliferation and survival.

   Evidence KLK2 overexpression and siRNA knockdown in LNCaP cells; AR reporter assays; xenograft growth

   PMID:24122203

   Open questions at the time

   • No direct physical interaction between KLK2 and ARA70 or AR demonstrated
   • Whether the protease activity of KLK2 is required for AR coactivation is unknown
   • Mechanism of G1 arrest upon KLK2 knockdown not delineated
6. 2019 Medium

   Discovery of a KLK2–FGFR2 gene fusion in metastatic prostate cancer showed that KLK2 regulatory elements can drive constitutive FGFR signaling, identifying a potential therapeutic vulnerability.

   Evidence Targeted RNA-seq identification; lentiviral expression in NIH3T3 cells; migration and drug sensitivity assays

   PMID:31043681

   Open questions at the time

   • Frequency of KLK2–FGFR2 fusions across prostate cancer cohorts not established
   • In vivo oncogenic potential of the fusion not tested in prostate models
7. 2024 Medium

   KLK2 was shown to cleave the IL-10R2 extracellular domain on macrophages, establishing a direct mechanism by which prostatic KLK2 promotes inflammation by disabling IL-10 signaling.

   Evidence FRET peptide library screening, FACS on bone-marrow-derived macrophages, cytokine and NO assays

   PMID:39106042

   Open questions at the time

   • Cleavage of IL-10R2 not demonstrated in human prostatic tissue or fluid
   • Whether KLK2-mediated IL-10R2 shedding contributes to prostate cancer immune evasion in vivo is unknown

• The structural determinants of KLK2 substrate specificity across its diverse substrates (pro-PSA, IGFBP-3, IL-10R2) remain undefined, and whether KLK2's intracellular/nuclear functions require its catalytic activity is unresolved.
• No crystal structure of KLK2 in complex with any substrate or inhibitor
• Catalytic vs. non-catalytic contributions to AR coactivation not separated
• In vivo relevance of cell-surface KLK2 expression not established