HTRA1

What is HTRA1 Protein?

You can find the enzyme protein HTRA1 in a bunch of different tissues, including the cells in the retina. It's actively involved in breaking down proteins surrounding cells, like fibronectin and TGF-β, to help remodel those spaces. This protein is linked to various health problems like age-related macular degeneration (AMD), a few brain disorders, and cancer. When it comes to AMD, tweaks in the HTRA1 gene promoter can heighten the chance of developing the condition. Plus, HTRA1 helps manage the TGF-β signaling pathway, which impacts how cells grow and change form.

What is the Function of HTRA1 Protein?

HTRA1 is a kind of enzyme protein with many biological roles. It helps reshape the area around cells by breaking down proteins like fibronectin and others related to cartilage. HTRA1 also tweaks the availability of insulin-like growth factors by cutting up binding proteins and stops signals from TGF-β family members. Inside the cell, HTRA1 can degrade TSC2, which activates other targets down the line. Because of all these jobs, HTRA1 is important in various body processes, like blood vessel growth in the retina, neuron survival and development, and even in the way cancer progresses.

HTRA1 Related Signaling Pathway

HTRA1 is a protein that gets involved in many signaling pathways, and it's pretty crucial in regulating the TGF-β pathway. It helps control TGF-β signals by breaking down a protein called LTBP1. On top of that, HTRA1 also plays a part in the Wnt/β-catenin pathway, which influences how cells grow and change. Because it manages these pathways, HTRA1 is key in processes like cell growth, how cells develop, and even how diseases progress.

HTRA1 Related Diseases

HTRA1 protein is linked to several diseases, especially small vessel disease in the brain and age-related macular degeneration (AMD). Mutations in the HTRA1 gene can cause conditions like CARASIL, an autosomal recessive brain artery disease with small strokes and white matter damage, and a dominant type of small vessel brain disease (CSVD). People with these conditions often experience white matter softening, small strokes, recurrent stroke episodes, and worsening memory or thinking skills. Additionally, HTRA1 plays a crucial role in AMD, with certain gene variations increasing the risk of developing this eye condition.

Bioapplications of HTRA1

HTRA1 protein is used in various fields like research, industrial production, and clinical studies. In research, scientists use HTRA1, a type of serine protease, to look into its role in reshaping the area around cells, controlling protein quality, and helping with cell signaling. Its influence in rheumatoid arthritis is also a subject of study, highlighting how it regulates inflammation. On the industrial side, companies create recombinant HTRA1 proteins and inhibitors for lab reagents and as tools for understanding its role in diseases. Clinically, HTRA1 is seen as a promising biomarker and potential treatment target for diseases like age-related macular degeneration, rheumatoid arthritis, and dilated cardiomyopathy.

Case Study 1: Lin X. et al. Int J Mol Sci. 2022

Researchers found that congenital cataracts are the top reason kids lose their vision globally. When it comes to posterior subcapsular congenital cataracts (PSC) in the key visual area, vision can get worse, and it might cause lazy eye or amblyopia. The exact cause of PSC isn't well understood yet. So, this study looked into how HTRA1 works in human lens cells. It turns out that in kids with PSC, HTRA1 levels dropped a lot compared to those without cataracts. HTRA1 usually helps block the TGF-β pathway, which is crucial for cataracts to form. The research showed that this pathway was active in the lens tissues of those with PSC. They checked how HTRA1 affected cell growth, movement, and death in lens cells. They found that lower HTRA1 helped cells grow and move by kicking the TGF-β/Smad pathway into gear, which then boosted the FN1 and α-SMA genes. In mouse eyes, removing HTRA1 led to more p-Smad2/3, activating the pathway, making cells grow and arrange irregularly, and eventually causing cataracts.

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  Fig1. Immunofluorescence images of HTRA1 staining in HLECs.
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  Fig2. Changes of HTRA1, p-Smad2/3, TGF-β1 and TGF-β2 gene expression detected by Western blotting

Case Study 2: Globus O. et al. Sci Rep. 2017

Researchers found that the incorrect activation of the Wnt signaling pathway is behind many cancers and other illnesses, especially colorectal cancer. β-catenin is the key protein here, working with TCF/LEF to turn on Wnt genes. They've spotted HTRA1, a serine protease, as a new part of this puzzle. HTRA1 can interfere with Wnt/β-catenin signaling, both inside and outside the cell, changing how certain Wnt genes behave. Plus, HTRA1 links up with β-catenin and helps cut down how fast cells multiply.

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  Fig3. HEK293T cells were transfected as in A along with HTRA1-HA, FLAG-β-catenin, or an empty HA vector.
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  Fig4. SW480 or HCT116 cell lysates were subjected to co-immunoprecipitation using an anti-β-catenin antibody or a non-specific IgG control.

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  Fig1. The nanoparticles could release lipopeptide C10-KR8 and Zn ions, interacting with Htra1 protein, or activating Htra1/FAK/YAP pathway to promote osteogenesis in vitro and in vitro. (Xuechun Wang, 2024)
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  Fig2. Mechanistic studies of HTRA1 associated with the tumor microenvironment. (Shina Song, 2024)

HTRA1 has several biochemical functions, for example, insulin-like growth factor binding,serine-type endopeptidase activity,serine-type peptidase activity. Some of the functions are cooperated with other proteins, some of the functions could acted by HTRA1 itself. We selected most functions HTRA1 had, and list some proteins which have the same functions with HTRA1. You can find most of the proteins on our site.

Function	Related Protein
serine-type endopeptidase activity	LOC100686744,PCSK7,PRSS23,MASP2,CTRB1,PRSS22,PCSK6,KLK10,PRSS41,PRSS2
insulin-like growth factor binding	WISP1B,HTRA1B,WISP1,IGFBP7,IGFALS,IGFBP5B,WISP2,IGF1R,HTRA1A,IGF1RA
serine-type peptidase activity	FURINB,HGFA,TMPRSS11E,DPP10,SEC11C,IMMP2L,F9B,KLK7,PLG,KLK12

HTRA1 has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with HTRA1 here. Most of them are supplied by our site. Hope this information will be useful for your research of HTRA1.

IMPDH1;NOS3;CSNK2B;FAM46A;yibD;GRB2;GOLT1B