Matriptase activation and shedding through PDGF-D-mediated extracellular acidosis

Najy, Abdo J.; Dyson, Gregory; Jena, Bhanu P.; Lin, Chen‐Yong; Kim, Hyeong-Reh Choi

doi:10.1152/ajpcell.00043.2015

Cited by 15 publications

(12 citation statements)

References 45 publications

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“…The shedding into the extracellular milieu may be particularly important for the role of matriptase in cancer. Within the tumor microenvironment, the shed active matriptase can activate its cancer-related substrates, including urokinase, HGF, and PDGF-D in the pericellular space, providing an important mechanism for cancer cells to interact with stromal cells [ 22 – 24 ].…”

Section: Introductionmentioning

confidence: 99%

Matriptase shedding is closely coupled with matriptase zymogen activation and requires de novo proteolytic cleavage likely involving its own activity

et al. 2017

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The type 2 transmembrane serine protease matriptase is involved in many pathophysiological processes probably via its enzymatic activity, which depends on the dynamic relationship between zymogen activation and protease inhibition. Matriptase shedding can prolong the life of enzymatically active matriptase and increase accessibility to substrates. We show here that matriptase shedding occurs via a de novo proteolytic cleavage at sites located between the SEA domain and the CUB domain. Point or combined mutations at the four positively charged amino acid residues in the region following the SEA domain allowed Arg-186 to be identified as the primary cleavage site responsible for matriptase shedding. Kinetic studies further demonstrate that matriptase shedding is temporally coupled with matriptase zymogen activation. The onset of matriptase shedding lags one minute behind matriptase zymogen activation. Studies with active site triad Ser-805 point mutated matriptase, which no longer undergoes zymogen activation or shedding, further suggests that matriptase shedding depends on matriptase zymogen activation, and that matriptase proteolytic activity may be involved in its own shedding. Our studies uncover an autonomous mechanism coupling matriptase zymogen activation, proteolytic activity, and shedding such that a proportion of newly generated active matriptase escapes HAI-1-mediated rapid inhibition by shedding into the extracellular milieu.

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Section: Introductionmentioning

confidence: 99%

Matriptase shedding is closely coupled with matriptase zymogen activation and requires de novo proteolytic cleavage likely involving its own activity

et al. 2017

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“…One key molecule responsible for extracellular acidosis is CAIX, whose main function in association with anion exporters is to catalyze metabolically released CO 2 , leading to increased H + gradient in the extracellular milieu and alkaline intracellular pH [22,27,66]. In fact, CAIX mediates extracellular acidification of prostate, colon, and ovarian cancer cells in vitro [34,67,68] and is overexpressed in tumor tissues of colorectal, ovarian, gastric, pancreatic, and breast cancer patients [25,69]. In the current study, we made an interesting observation that increased TIMP-1 expression and its activity via CD63 correlate with malignant phenotypes of breast carcinoma using the MCF10A progression model.…”

Section: Discussionmentioning

confidence: 99%

“…Cells were grown to confluence, washed with warm PBS, then cultured with a HEPESbuffered phenol-red free DMEM (Thermo Fisher Scientific) for 16 h. pH was assessed as described by Najy et al [34] where conditioned media were collected, and the cell debris was removed by centrifugation at 2000 RPM for 5 min. The pH of the conditioned media was measured using a Beckman φ300 Digital pH Meter, and pH readouts were subtracted from the pH at time zero to determine changes in extracellular pH, which were further normalized to the live cell numbers (10 6 cells).…”

Section: Extracellular Ph Analysismentioning

confidence: 99%

Regulation of Tumor Metabolism and Extracellular Acidosis by the TIMP-10–CD63 Axis in Breast Carcinoma

Najy

Jung

Kim

et al. 2021

Cells

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A hallmark of malignant solid tumor is extracellular acidification coupled with metabolic switch to aerobic glycolysis. Using the human MCF10A progression model of breast cancer, we show that glycolytic switch and extracellular acidosis in aggressive cancer cells correlate with increased expression of tissue inhibitor of metalloproteinase-1 (TIMP-1), known to induce intracellular signal transduction through the interaction with its cell surface receptor CD63, independent of its metalloproteinase inhibitory function. We found that, in aggressive breast carcinoma, the TIMP-1–CD63 signaling axis induced a metabolic switch by upregulating the rate of aerobic glycolysis, lowering mitochondrial respiration, preventing intracellular acidification, and inducing extracellular acidosis. Carbonic anhydrase IX (CAIX), a regulator of cellular pH through the hydration of metabolically released pericellular CO2, was identified as a downstream mediator of the TIMP-1–CD63 signaling axis responsible for extracellular acidosis. Consistently with our previous study, the TIMP-1–CD63 signaling promoted survival of breast cancer cells. Interestingly, breast carcinoma cell survival was drastically reduced upon shRNA-mediated knockdown of CAIX expression, demonstrating the significance of CAIX-regulated pH in the TIMP-1–CD63-mediated cancer cell survival. Taken together, the present study demonstrates the functional significance of TIMP-1–CD63–CAXI signaling axis in the regulation of tumor metabolism, extracellular acidosis, and survival of breast carcinoma. We propose that this axis may serve as a novel therapeutic target.

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“…In general, shedding from cell membrane increases the duration of matriptase activation and the accessibility of matriptase to its substrates. The shed matriptase contains the catalytic ectodomain and in tumour microenvironment may more readily activate oncogenic substrates and change the ECM contributing to tumour progression . 3‐Cl‐AHPC also induces matriptase shedding (Figure B), but it is not certain whether 3‐Cl‐AHPC‐induced matriptase/HAI‐1 complex formation and shedding are correlative or not.…”

Section: Discussionmentioning

confidence: 99%

3‐Cl‐AHPC inhibits pro‐HGF maturation by inducing matriptase/HAI‐1 complex formation

Chen

Liu

et al. 2018

J Cellular Molecular Medi

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Matriptase is an epithelia‐specific membrane‐anchored serine protease, and its dysregulation is highly related to the progression of a variety of cancers. Hepatocyte growth factor activator inhibitor‐1 (HAI‐1) inhibits matriptase activity through forming complex with activated matriptase. The balance of matriptase activation and matriptase/HAI‐1 complex formation determines the intensity and duration of matriptase activity. 3‐Cl‐AHPC, 4‐[3‐(1‐adamantyl)‐4‐hydroxyphenyl]‐3‐chlorocinnamic acid, is an adamantly substituted retinoid‐related molecule and a ligand of retinoic acid receptor γ (RARγ). 3‐Cl‐AHPC is of strong anti‐cancer effect but with elusive mechanisms. In our current study, we show that 3‐Cl‐AHPC time‐ and dose‐ dependently induces matriptase/HAI‐1 complex formation, leading to the suppression of activated matriptase in cancer cells and tissues. Furthermore, 3‐Cl‐AHPC promotes matriptase shedding but without increasing the activity of shed matriptase. Moreover, 3‐Cl‐AHPC inhibits matriptase‐mediated cleavage of pro‐HGF through matriptase/HAI‐1 complex induction, resulting in the suppression of pro‐HGF‐stimulated signalling and cell scattering. Although 3‐Cl‐AHPC binds to RARγ, its induction of matriptase/HAI‐1 complex is not RARγ dependent. Together, our data demonstrates that 3‐Cl‐AHPC down‐regulates matriptase activity through induction of matriptase/HAI‐1 complex formation in a RARγ‐independent manner, providing a mechanism of 3‐Cl‐AHPC anti‐cancer activity and a new strategy to inhibit abnormal matriptase activity via matriptase/HAI‐1 complex induction using small molecules.

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Matriptase activation and shedding through PDGF-D-mediated extracellular acidosis

Abstract: Najy AJ, Dyson G, Jena BP, Lin CY, Kim HR. Matriptase activation and shedding through PDGF-D-mediated extracellular acidosis.

Cited by 15 publications

References 45 publications

Matriptase shedding is closely coupled with matriptase zymogen activation and requires de novo proteolytic cleavage likely involving its own activity

Matriptase shedding is closely coupled with matriptase zymogen activation and requires de novo proteolytic cleavage likely involving its own activity

Regulation of Tumor Metabolism and Extracellular Acidosis by the TIMP-10–CD63 Axis in Breast Carcinoma

3‐Cl‐AHPC inhibits pro‐HGF maturation by inducing matriptase/HAI‐1 complex formation

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