Trp 250 ‐h K 2 is defective in intracellular trafficking and activates the unfolded protein response

hK 2, a member of the kallikrein protease family encoded by KLK 2 , 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 KLK 2 , codes for W‐ hK 2 and is associated with lower serum hK 2 levels and higher risk of prostate cancer than the C allele encoding R‐ hK 2. To elucidate the mechanism that underlies this SNP 's function, we transfected plasmids expressing R‐ hK 2 or W‐ hK 2 into PC 3, HeLa and HEK 293A cells and measured the hK 2 level in cell lysates and conditioned media. The level of W‐ hK 2 was lower than R‐ hK 2 in conditioned media but was not different from R‐ hK 2 in cell lysates. W‐ hK 2 was hardly colocalized with Golgi‐targeted fluorescent protein whereas R‐ hK 2 colocalized. Reporter assays related to the unfolded protein response ( UPR ) and phospho‐ eIF 2α immunoblot showed that W‐ hK 2 increased UPR activity more than R‐ hK 2. These results indicated that W‐ hK 2 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.