The human homolog of the E. Coli htrA gene product, HtrA, is identified in osteoarthritic cartilage and is repressed in SV40-transformed fibroblast. The gene encoding HtrA protein is highly conserved among mammalian species and belongs to the serine protease family. The HtrA protein contains an IGF-binding domain and exhibits endoproteolytic activity, including autocatalytic cleavage. HtrA is a secreted protein that is expressed in heterologous systems. HtrA plays a role in the degradation of denatured proteins and cell growth regulation. Human HtrA2 (also designated Omi), a novel member of the HtrA serine protease family, is highly homologous to HtrA (also known as L56 and HtrA1). HtrA2 is a ubiquitously expressed nuclear protease that is capable of autoproteolysis. The HtrA2 protein exists as two polypeptides and as an alternatively spliced form called D-Omi, which is predominately expressed in the kidney, colon and thyroid. Due to a modified PDZ domain, D-Omi does not interact with the known partner of HtrA2, the Mxi2 protein. Like HtrA, HtrA2 is involved in the degradation aberrantly folded proteins during conditions of cellular stress, suggesting that it may possess a chaperone-like role under normal conditions.