Recombinant Human Serine protease HTRA1 (HTRA1)

Function

Serine protease with a variety of targets, including extracellular matrix proteins such as fibronectin. HTRA1-generated fibronectin fragments further induce synovial cells to up-regulate MMP1 and MMP3 production. May also degrade proteoglycans, such as aggrecan, decorin and fibromodulin. Through cleavage of proteoglycans, may release soluble FGF-glycosaminoglycan complexes that promote the range and intensity of FGF signals in the extracellular space. Regulates the availability of insulin-like growth factors (IGFs) by cleaving IGF-binding proteins. Inhibits signaling mediated by TGF-beta family members. This activity requires the integrity of the catalytic site, although it is unclear whether TGF-beta proteins are themselves degraded. By acting on TGF-beta signaling, may regulate many physiological processes, including retinal angiogenesis and neuronal survival and maturation during development. Intracellularly, degrades TSC2, leading to the activation of TSC2 downstream targets

Subcellular Location

Cell membrane; Secreted; Cytoplasm, cytosol

Disease Association

[A variant in the HTRA1 promoter may be associated with increased risk for developing age-related macular degeneration (ARMD), a multifactorial eye disease and common cause of vision loss] | Cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 2 (CARASIL2) : A cerebrovascular disease characterized by non-hypertensive arteriopathy of cerebral small vessels with subcortical infarcts, alopecia, and spondylosis. Small cerebral arteries show arteriosclerotic changes, fibrous intimal proliferation, and hyaline degeneration with splitting of the intima and/or the internal elastic membrane. Neurologic features include progressive dementia, gait disturbances, extrapyramidal and pyramidal signs, and demyelination of the cerebral white matter with sparing of U fibers. [The disease is caused by variants affecting the gene represented in this entry] | Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, 2 (CADASIL2) : A cerebrovascular disease characterized by multiple subcortical infarcts, pseudobulbar palsy, dementia, and the presence of granular deposits in small cerebral arteries producing ischemic stroke. [The disease is caused by variants affecting the gene represented in this entry]

Tissue Specificity

Widely expressed, with strongest expression in placenta (at protein level). Secreted by synovial fibroblasts. Up-regulated in osteoarthritis and rheumatoid arthritis synovial fluids and cartilage as compared with non-arthritic (at protein level)

Subunit

Forms homotrimers. In the presence of substrate, may form higher-order multimers in a PDZ-independent manner. Interacts with TGF-beta family members, including BMP4, TGFB1, TGFB2, activin A and GDF5 (By similarity)

• Zumbrunn J. et al. Primary structure of a putative serine protease specific for IGF-binding proteins. — FEBS Lett. (1996)
• Crowl R.M. et al. Genomic organization and promoter characterization of the human HTRA (PRSS11) gene. (JUN-)
• Mural R.J. et al. PubMed: CI-5GBD0VIIJ7C63 (SEP-)
• Hu S.I. et al. Human HtrA, an evolutionarily conserved serine protease identified as a differentially expressed gene product in osteoarthritic cartilage. — J. Biol. Chem. (1998)
• De Luca A. et al. The serine protease HtrA1 is upregulated in the human placenta during pregnancy. — J. Histochem. Cytochem. (2004)
• Grau S. et al. The role of human HtrA1 in arthritic disease. — J. Biol. Chem. (2006)
• Dewan A. et al. HTRA1 promoter polymorphism in wet age-related macular degeneration. — Science (2006)
• Yang Z. et al. A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration. — Science (2006)