Processing of Wild-type and Mutant Proinsulin-like Growth Factor-IA by Subtilisin-related Proprotein Convertases

Duguay, Stephen J.; Milewski, Wieslawa; Young, Bryan D.; Nakayama, Kazuhisa; Steiner, Donald F.

doi:10.1074/jbc.272.10.6663

Cited by 89 publications

(70 citation statements)

References 28 publications

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“…The processing of proMT1-MMP by furin is consistent with the ability of this proprotein convertase to recognize RX(K/R)R, RXXR, KXXR, or RR motifs (Duguay et al, 1997;Nakayama, 1997;Cui et al, 1998;Zhou et al, 1999). Unexpectedly, however, MT1-MMP was processed after cleavage immediately downstream of the 108 RRKR motif in the furindeficient RPE.40 cell line by a predominately ␣ 1 PDX-sensitive process.…”

Section: Proprotein Convertases As Processing Enzymes For Mt1-mmpmentioning

confidence: 62%

“…However, furin-deficient cell lines have proven to be a useful adjunct for discriminating between furin-dependent and furin-independent processing pathways (Pei and Weiss, 1995;Duguay et al, 1997;Inocencio et al, 1997;Logeat et al, 1998). As expected, neither of the well-characterized furin-deficient cell lines, LoVo or RPE.40, processed soluble ⌬MT1-MMP to its mature form.…”

Section: Proprotein Convertases As Processing Enzymes For Mt1-mmpmentioning

confidence: 97%

“…The ␣ 1 PDX-inhibitable proprotein convertase responsible for wild-type MT1-MMP processing has not been identified. However, in contrast to LoVo cells, RPE.40 cells do express PC6 (as both the transmembrane-anchored and soluble forms, PC6B and P6CA, respectively; Duguay et al, 1997). Interestingly, PC6, like furin, can process RXKR-, RXXR-, and KXXR-containing molecules (Zarkik et al, 1997;Cui et al, 1998).…”

Section: Proprotein Convertases As Processing Enzymes For Mt1-mmpmentioning

confidence: 99%

“…Given that the secondary site within 86 KXXR-RXR was apparently used only when the primary 108 RRKR motif was mutated, a physiological role for the alternative site has not been demonstrated in transfected cells. Nonetheless, primary and secondary cleavage sites for proprotein convertases have been posited in other target molecules, including Notch, bone morphogenic protein-4, and insulin growth factor-1 (Duguay et al, 1997;Cui et al, 1998;Logeat et al, 1998).…”

Section: A Role For Multibasic Motifs In Mt1-mmp Processingmentioning

confidence: 99%

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Regulation of Membrane Type-1 Matrix Metalloproteinase Activation by Proprotein Convertases

Yana

Weiss

2000

MBoC

278

271

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Membrane type-1 matrix metalloproteinase (MT1-MMP) is the prototypical member of a subgroup of membrane-anchored proteinases that belong to the matrix metalloproteinase family. Although synthesized as a zymogen, MT1-MMP plays an essential role in extracellular matrix remodeling after an undefined process that unmasks its catalytic domain. We now report the existence of a proprotein convertase-MT1-MMP axis that regulates the processing and functional activity of the metalloproteinase. Two sets of basic motifs in the propeptide region of MT1-MMP are identified that potentially can be recognized by the proprotein convertase family of subtilisinlike proteases. Processing of proMT1-MMP as well as the expression of its proteolytic activity were blocked by mutating these recognition motifs or by inhibiting the proprotein convertases furin and PC6 with the serpin-based inhibitor ␣ 1 antitrypsin Portland. Furthermore, both furindependent and furin-independent MT1-MMP processing pathways are identified that require tethering of the metalloproteinase to the cell surface. These findings demonstrate the existence of a proprotein convertase-MT1-MMP axis that can regulate extracellular matrix remodeling.

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Section: Proprotein Convertases As Processing Enzymes For Mt1-mmpmentioning

confidence: 62%

Section: Proprotein Convertases As Processing Enzymes For Mt1-mmpmentioning

confidence: 97%

Section: Proprotein Convertases As Processing Enzymes For Mt1-mmpmentioning

confidence: 99%

Section: A Role For Multibasic Motifs In Mt1-mmp Processingmentioning

confidence: 99%

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Regulation of Membrane Type-1 Matrix Metalloproteinase Activation by Proprotein Convertases

Yana

Weiss

2000

MBoC

278

271

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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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Stable Expression of Soluble Therapeutic Peptides in Eukaryotic Cells by Multimerisation: Application to the HIV‐1 Fusion Inhibitory Peptide C46

et al. 2006

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A major drawback of therapeutic peptides is their short half-life, which results in the need for multiple applications and high synthesis costs. To overcome this, we established a eukaryotic expression system that allows the stable expression of small therapeutic peptides by multimerisation. By inserting the sequence encoding the therapeutic peptide between a signal peptide and the multimerising domain of the alpha-chain from the human C4bp plasma protein, therapeutic peptides as small as 5 kDa are secreted as multimers from transfected cells; this allows easy purification. As proof of principle, we show that the T20-derived HIV-1 fusion inhibitory peptide C46 in its multimeric form: i) was efficiently secreted, ii) was more stable than the current antiviral drug T20 in vitro and in vivo, and iii) inihibited HIV-1 entry with similar efficiency in vitro. Besides the gain in stability, multimerisation also leads to increased valency and allows the combination of several therapeutic functions. Furthermore, by expressing the multimers from cells, post-translational modifications could easily be introduced.

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Processing of Wild-type and Mutant Proinsulin-like Growth Factor-IA by Subtilisin-related Proprotein Convertases

Abstract: Insulin-like growth factor I (IGF-I

Cited by 89 publications

References 28 publications

Regulation of Membrane Type-1 Matrix Metalloproteinase Activation by Proprotein Convertases

Regulation of Membrane Type-1 Matrix Metalloproteinase Activation by Proprotein Convertases

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

Stable Expression of Soluble Therapeutic Peptides in Eukaryotic Cells by Multimerisation: Application to the HIV‐1 Fusion Inhibitory Peptide C46

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