HtrA4 Protease Promotes Chemotherapeutic-Dependent Cancer Cell Death

Wenta, Tomasz; Rychłowski, Michał; Jarzab, Miroslaw; Lipińska, Barbara

doi:10.3390/cells8101112

Cited by 17 publications

(20 citation statements)

References 39 publications

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“…Genetic variation within the ARMS2/HTRA1 locus strongly correlates with an increased risk for both neovascular AMD and GA 2,7,8 .HTRA1 is a secreted protease composed of an N-terminal IGFBPdomain, a Kazal-like domain, a central trypsin-like serine protease domain and a C-terminal PDZ domain 9 . There are four closely related HTRA family members in humans, HTRA1-4, all of which share a conserved protease domain 10 and have been implicated in various pathologies [11][12][13][14][15][16][17] . HTRA1 itself cleaves a plethora of substrates and is linked to several pathogenic and developmental processes, including cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), AMD, Alzheimer's disease, osteoarthritis, neuronal development, and tumor progression 8,13,17-20 .…”

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confidence: 99%

Allosteric inhibition of HTRA1 activity by a conformational lock mechanism to treat age-related macular degeneration

Gerhardy¹,

Ultsch²,

Tang³

et al. 2022

Nat Commun

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The trimeric serine protease HTRA1 is a genetic risk factor associated with geographic atrophy (GA), a currently untreatable form of age-related macular degeneration. Here, we describe the allosteric inhibition mechanism of HTRA1 by a clinical Fab fragment, currently being evaluated for GA treatment. Using cryo-EM, X-ray crystallography and biochemical assays we identify the exposed LoopA of HTRA1 as the sole Fab epitope, which is approximately 30 Å away from the active site. The cryo-EM structure of the HTRA1:Fab complex in combination with molecular dynamics simulations revealed that Fab binding to LoopA locks HTRA1 in a non-competent conformational state, incapable of supporting catalysis. Moreover, grafting the HTRA1-LoopA epitope onto HTRA2 and HTRA3 transferred the allosteric inhibition mechanism. This suggests a conserved conformational lock mechanism across the HTRA family and a critical role of LoopA for catalysis, which was supported by the reduced activity of HTRA1-3 upon LoopA deletion or perturbation. This study reveals the long-range inhibition mechanism of the clinical Fab and identifies an essential function of the exposed LoopA for activity of HTRA family proteases.

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mentioning

confidence: 99%

Allosteric inhibition of HTRA1 activity by a conformational lock mechanism to treat age-related macular degeneration

Gerhardy¹,

Ultsch²,

Tang³

et al. 2022

Nat Commun

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“…Studies have explored the potential role of HtrA4 in cancer cell lines, reporting that HtrA4 promotes cell death by degrading XIAP and pro-caspase 7, which was shown previously for HtrA1 and 3 in cancer cells [ 88 , 89 ]. Several other proteins have also been identified as potential substrates of HtrA4, notably cytoskeleton proteins actin and tubulin, TCP1 chaperonin and S100A6 calcium-binding protein, through which HtrA4 may exert an effect on cytoskeleton homeostasis [ 90 ].…”

Section: Function Regulation and Potential Substrates Of Human Htras And Their Involvement Of Various Diseasesmentioning

confidence: 70%

Overview of Human HtrA Family Proteases and Their Distinctive Physiological Roles and Unique Involvement in Diseases, Especially Cancer and Pregnancy Complications

Wang

Nie

2021

IJMS

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The mammalian high temperature requirement A (HtrA) proteins are a family of evolutionarily conserved serine proteases, consisting of four homologs (HtrA1-4) that are involved in many cellular processes such as growth, unfolded protein stress response and programmed cell death. In humans, while HtrA1, 2 and 3 are widely expressed in multiple tissues with variable levels, HtrA4 expression is largely restricted to the placenta with the protein released into maternal circulation during pregnancy. This limited expression sets HtrA4 apart from the rest of the family. All four HtrAs are active proteases, and their specific cellular and physiological roles depend on tissue type. The dysregulation of HtrAs has been implicated in many human diseases such as cancer, arthritis, neurogenerative ailments and reproductive disorders. This review first discusses HtrAs broadly and then focuses on the current knowledge of key molecular characteristics of individual human HtrAs, their similarities and differences and their reported physiological functions. HtrAs in other species are also briefly mentioned in the context of understanding the human HtrAs. It then reviews the distinctive involvement of each HtrA in various human diseases, especially cancer and pregnancy complications. It is noteworthy that HtrA4 expression has not yet been reported in any primary tumour samples, suggesting an unlikely involvement of this HtrA in cancer. Collectively, we accentuate that a better understanding of tissue-specific regulation and distinctive physiological and pathological roles of each HtrA will improve our knowledge of many processes that are critical for human health.

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“…HtrA family proteins are involved in several cellular processes, including apoptosis and unfolded protein stress response [ 33 ]. A recent study suggested that the expression of HTRA4 enhances the effect of chemotherapy in breast and lung cancer cell lines [ 34 ]. AXL, a member of the TAM receptor tyrosine kinase family (TYRO3, AXL, and MER), is well known for its roles in cell proliferation, migration, invasion, and survival.…”

Section: Resultsmentioning

confidence: 99%

A Receptor Tyrosine Kinase Inhibitor Sensitivity Prediction Model Identifies AXL Dependency in Leukemia

Nasimian

Ashiri

Ahmed

et al. 2023

IJMS

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Despite incredible progress in cancer treatment, therapy resistance remains the leading limiting factor for long−term survival. During drug treatment, several genes are transcriptionally upregulated to mediate drug tolerance. Using highly variable genes and pharmacogenomic data for acute myeloid leukemia (AML), we developed a drug sensitivity prediction model for the receptor tyrosine kinase inhibitor sorafenib and achieved more than 80% prediction accuracy. Furthermore, by using Shapley additive explanations for determining leading features, we identified AXL as an important feature for drug resistance. Drug−resistant patient samples displayed enrichment of protein kinase C (PKC) signaling, which was also identified in sorafenib−treated FLT3−ITD−dependent AML cell lines by a peptide−based kinase profiling assay. Finally, we show that pharmacological inhibition of tyrosine kinase activity enhances AXL expression, phosphorylation of the PKC−substrate cyclic AMP response element binding (CREB) protein, and displays synergy with AXL and PKC inhibitors. Collectively, our data suggest an involvement of AXL in tyrosine kinase inhibitor resistance and link PKC activation as a possible signaling mediator.

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HtrA4 Protease Promotes Chemotherapeutic-Dependent Cancer Cell Death

Cited by 17 publications

References 39 publications

Allosteric inhibition of HTRA1 activity by a conformational lock mechanism to treat age-related macular degeneration

Allosteric inhibition of HTRA1 activity by a conformational lock mechanism to treat age-related macular degeneration

Overview of Human HtrA Family Proteases and Their Distinctive Physiological Roles and Unique Involvement in Diseases, Especially Cancer and Pregnancy Complications

A Receptor Tyrosine Kinase Inhibitor Sensitivity Prediction Model Identifies AXL Dependency in Leukemia

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