Trp(250) -hK2 is defective in intracellular trafficking and activates the unfolded protein response.

hK2, a member of the kallikrein protease family encoded by KLK2, is expressed exclusively in prostate and is a putative adjunct tumor marker for prostate cancer screening. The T allele of rs198977, a single nucleotide polymorphism in exon 5 of KLK2, codes for W-hK2 and is associated with lower serum hK2 levels and higher risk of prostate cancer than the C allele encoding R-hK2. To elucidate the mechanism that underlies this SNP's function, we transfected plasmids expressing R-hK2 or W-hK2 into PC3, HeLa and HEK293A cells and measured the hK2 level in cell lysates and conditioned media. The level of W-hK2 was lower than R-hK2 in conditioned media but was not different from R-hK2 in cell lysates. W-hK2 was hardly colocalized with Golgi-targeted fluorescent protein whereas R-hK2 colocalized. Reporter assays related to the unfolded protein response (UPR) and phospho-eIF2α immunoblot showed that W-hK2 increased UPR activity more than R-hK2. These results indicated that W-hK2 had a defect in cellular trafficking from the ER to the Golgi complex due to its misfolding and that it activated the UPR, suggesting a mechanism to explain the association of the T allele with higher prostate cancer risk.