Proteolytic processing of the hepatocyte growth factor/scatter factor receptor by furin

Komada, Masayuki; Hatsuzawa, Kiyotaka; Shibamoto, Sayumi; Ito, F.; Nakayama, Kazuhisa; Kitamura, Naomi

doi:10.1016/0014-5793(93)80958-w

Cited by 124 publications

(82 citation statements)

References 42 publications

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“…Furin can process and activate other cancerassociated substrates not directly involved in invasion or degradation of ECM such as growth factors and growth factor receptors. [31][32][33][34] Inhibition of furin by PDX, a specific inhibitor of this PC, resulted in a reduction in proliferation rate in HT-29, a colon carcinoma cell line. 17 To elucidate if overexpression of furin in HNSCC was related to enhanced proliferation, [ 3 H]-thymidine incorporation experiments were performed.…”

Section: In Vivo Invasion Assays Confirmed the Results Obtained In Vitromentioning

confidence: 99%

Increased Furin Activity Enhances the Malignant Phenotype of Human Head and Neck Cancer Cells

Bassi¹,

Mahloogi²,

Cicco³

et al. 2003

The American Journal of Pathology

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Many proteins are synthesized as inactive proforms requiring a proteolytic processing to render them active. A variety of proteases catalyze these cleavage reactions. Proprotein convertases are a family of serine proteases capable of activating substrates that will subsequently intervene in extracellular matrix (ECM) degradation, cell growth, differentiation and viral pathogenesis. Furin, the prototype of this family, has been implicated in many physiological and pathological processes. Some of its substrates such as TGF-␤, MT-MMP's, and IGFR-1 have been identified. Overexpression of furin has been observed in several human tumors. In this report we demonstrate that overexpression of furin causes a significant increase in the invasive potential of human tumor cells of low and moderate aggressive potential in vitro and in vivo. SCC12 and SCC15 were transfected with furin cDNA, resulting in efficient processing of furin substrates. An in vivo invasion assay showed enhancement of invasive ability. Inhibition of furin activity with the synthetic inhibitor decanoyl-Arg-Val-Lys-Argchloromethyl-ketone, CMK, showed a significant decrease in both processing and in vitro invasiveness. A moderate enhancement in proliferation rate was observed when cells were transfected with furin. CMK treatment resulted in a marked reduction of this effect. Tumors obtained after subcutaneous (s.c.) inoculation of furin-overexpressing cells were larger and developed earlier than the controls. Furin overexpression caused an imbalance in the activation of invasion and proliferation-related substrates leading to the acquisition of an advanced malignant phenotype. In addition, inhibition of furin activity decreases substrate activation, proliferation rate, and invasive potential of cancer cells, suggesting that furin is a potentially useful target for therapeutics.

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Section: In Vivo Invasion Assays Confirmed the Results Obtained In Vitromentioning

confidence: 99%

Increased Furin Activity Enhances the Malignant Phenotype of Human Head and Neck Cancer Cells

Bassi¹,

Mahloogi²,

Cicco³

et al. 2003

The American Journal of Pathology

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“…Because CHO cells are known to express most other PCs, it is evident that they cannot substitute for furin in the PV infectious process (13). Additionally, we examined a second furin-deficient line, LoVo, a human colon carcinoma cell line that is defective in proprotein processing because of a point mutation within both alleles of the furin gene (14). We found that these cells are incapable of supporting PV infection until a functional furin gene is provided by transfection (data not shown).…”

Section: Susceptibility Of Pv Infection To Pc Inhibitionmentioning

confidence: 99%

Cleavage of the papillomavirus minor capsid protein, L2, at a furin consensus site is necessary for infection

Richards

Lowy

Schiller

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

304

334

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Papillomaviruses (PV) comprise a large family of nonenveloped DNA viruses that include the oncogenic PV types that are the causative agents of human cervical cancer. As is true of many animal DNA viruses, PV are taken into the cell by endocytosis and must escape from the endosomal compartment to the cytoplasm to initiate infection. Here we show that this step depends on the site-specific enzymatic cleavage of the PV minor virion protein L2 at a consensus furin recognition site. Cleavage by furin, a cellencoded proprotein convertase, is known to be required for endosome escape by many bacterial toxins. However, to our knowledge, furin has not been previously implicated in the viral entry process. This step is potentially a target for PV inhibition.proprotein convertase

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“…similar amounts of receptor ( Figure 3B). Interestingly, this receptor, which is a PCs substrate, 34 was cleaved in PDX39P cells, indicating that other PCs than PC5A or furin may be involved in its endoproteolytic processing. This also demonstrates that the enhanced effect of HGF on cell migration is not due to a defect in receptor maturation.…”

Section: Proprotein Convertases Inhibition Increases Cell Migrationmentioning

confidence: 99%

Inhibition of Proprotein Convertases Enhances Cell Migration and Metastases Development of Human Colon Carcinoma Cells in a Rat Model

Nejjari

Berthet

Rigot

et al. 2004

The American Journal of Pathology

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Although proprotein convertases are involved in tumor development, nothing is known about their role in metastatic dissemination. To investigate the involvement of convertase inhibition, we used human colon carcinoma cells overexpressing ␣1-antitrypsin Portland (␣1-PDX, PDX39P cells), a potent convertase inhibitor. We previously reported that these cells bear uncleaved integrin ␣ subunits and display an altered attachment to vitronectin that is correlated with defects in the intracellular signaling pathways activated by ␣v␤5 integrin ligation. In this study, we demonstrate that the inhibition of proprotein convertase activity either by overexpression of ␣1-PDX or with the synthetic inhibitor decanoyl-Arg-Val-Lys-Arg-chloromethylketone (dec-RVKR-cmk) led to a significant increase in cell migration supported by the ␣v␤5 integrin. A collagen gel invasion assay showed that PDX39P cells also displayed an invasive ability, contrary to control cells. Moreover, when injected to immunosuppressed newborn rats, PDX39P cells were highly invasive, as they induce 10 times more metastases than mock-transfected cells. In addition, the aggressiveness of PDX39P cells can be greatly reduced by a function-blocking monoclonal antibody (mAb) against the ␣v subunit. It thus seems that inhibition of proprotein convertases enhances the in vivo invasiveness of colon tumor cells likely due to an increase in cell migration mediated by ␣v integrins. The acquisition of cell motility and the capacity to invade basement matrix membranes and adjacent tissues play a central role in the complex multi-step process of metastasis. Cell migration is the result of dynamic interactions between the cell, the extracellular matrix (ECM), and the cytoskeleton. Integrins connect the ECM proteins outside to the actin cytoskeleton within the cell, allowing the traction required for cell migration. 1,2 Integrins also play a crucial role in signal transduction events that control anchorage-independent growth and survival of tumor cells (for reviews, see references [3][4][5] ). Therefore, these adhesion molecules play a pivotal role in tumor cell invasion and metastasis. [5][6][7] Integrins are heterodimeric proteins composed by the non-covalent association of ␣ and ␤ subunits. Some integrin ␣ chains undergo a post-translational cleavage in their extracellular domain by furin and PC5A, two proprotein convertases (PCs) of the subtilisin/kexin family. 8,9 The role of this cleavage in integrin function remains unclear. Arguably, this post-translational processing of the ␣ chain is not required for ligand binding, 10 -12 but is essential for the signaling function of ␣6␤1 and ␣v␤5 integrins. 10,13 Moreover, recent data suggest that the ␣6 subunit cleavage might be linked to the differentiation state of lens cells. 14 PCs are responsible for the biological activation of a variety of precursor proteins, including pro-hormones and their receptors and adhesion molecules. They are ubiquitously expressed and are involved in many physiological and pathological processes. ...

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Proteolytic processing of the hepatocyte growth factor/scatter factor receptor by furin

Cited by 124 publications

References 42 publications

Increased Furin Activity Enhances the Malignant Phenotype of Human Head and Neck Cancer Cells

Increased Furin Activity Enhances the Malignant Phenotype of Human Head and Neck Cancer Cells

Cleavage of the papillomavirus minor capsid protein, L2, at a furin consensus site is necessary for infection

Inhibition of Proprotein Convertases Enhances Cell Migration and Metastases Development of Human Colon Carcinoma Cells in a Rat Model

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