KLK6

Kallikrein-related peptidase 6 (KLK6) is a secreted serine protease that regulates extracellular proteolytic activity and influences cell signaling^[1][2]. Mechanistically, KLK6 activates protease-activated receptor 2 (PAR2), leading to intracellular calcium flux and phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), which promotes cell proliferation, migration, and spheroid compaction^[1]. KLK6 expression is highly upregulated in colorectal cancer (CRC) and correlates with aggressive tumor phenotypes, including peritoneal metastasis, whereas its expression is absent in normal epithelia^[1]. Compared with related KLK isoforms, KLK6 demonstrates distinct substrate specificity and cellular signaling effects, highlighting its unique role in cancer-associated proteolytic cascades^[1][2]. Experimental models using cell-based invasion assays and combinatorial engineering of KLK6 inhibitors, such as APPI-4M, show that targeted inhibition can suppress KLK6-mediated invasion while exhibiting high proteolytic stability and isoform selectivity^[2]. These findings suggest that KLK6 is a viable target for therapeutic intervention and biomarker development, with its inhibitors applicable for both mechanistic studies and potential translational applications^[2]. Furthermore, KLK6 participates in broader proteolytic networks, interacting with other kallikreins and influencing disease-relevant pathways, providing a foundation for precision-targeted drug design^[1][2].