Characterization of human c-fes/fps reveals a new transcription unit (fur) in the immediately upstream region of the proto-oncogene

Roebroek, Anton; Schalken, Jack A.; Bussemakers, M. J. G.; Heerikhuizen, Harm van; Onnekink, Carla; Debruyne, F.M.J.; Bloemers, H. P. J.; Ven, Wim J.M. Van de

doi:10.1007/bf00364823

Cited by 92 publications

(52 citation statements)

References 35 publications

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“…1 has been previously cloned from a human genomic library (12) and completely sequenced, with the exception of approximately 1 kb at the 3' end (22). The proposed intron-exon structure is based on comparison with known avian and feline viral sequences (22) and c-fps/fes cDNAs (33; P. Greer, unpublished data). The gene consists of 18 coding exons (numbered 2 through 19) with a single first noncoding exon.…”

Section: Resultsmentioning

confidence: 99%

Myeloid expression of the human c-fps/fes proto-oncogene in transgenic mice.

Greer¹,

Maltby²,

Rossant³

et al. 1990

Mol. Cell. Biol.

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The mammalian c-fps/fes proto-oncogene encodes a 92-kilodalton cytoplasmic protein-tyrosine kinase (p92c-fes), which is expressed in immature and differentiated hematopoietic cells of the myeloid lineage. To determine the limits of the c-fps/fes locus and to investigate the cis-acting sequences required to direct appropriate tissue-specific expression, a 13-kilobase-pair fragment of human genomic DNA containing the entire c-fps/fes coding sequence was introduced into the mouse germ line. Transcription of the human c-fps/fes transgene was highest in bone marrow and showed a tissue distribution identical to that of the endogenous mouse gene. Macrophages cultured from transgenic mouse bone marrow contained particularly high levels of human and murine c-fps/fes RNA. Furthermore, expression of human c-fps/fes RNA induced a proportionate increase in the level of the p92c-fes protein-tyrosine kinase in bone marrow, bone marrow-derived macrophages, and spleen. Elevated levels of normal human p92c-fes had no obvious effect on mouse development or hematopoiesis. Remarkably, given the short 5'- and 3'-flanking sequences, expression of the human proto-oncogene in bone marrow was independent of integration site, was proportional to the transgene copy number, and was of comparable efficiency to that of the endogenous mouse c-fps/fes gene. The 13-kilobase-pair fragment therefore defines a genetic locus sufficient for the appropriate tissue-specific expression of the fps/fes protein-tyrosine kinase and includes a dominant cis-acting element that directs integration-independent myeloid expression in transgenic mice.

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Section: Resultsmentioning

confidence: 99%

Myeloid expression of the human c-fps/fes proto-oncogene in transgenic mice.

Greer¹,

Maltby²,

Rossant³

et al. 1990

Mol. Cell. Biol.

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“…Because Kex2 could also correctly process mammalian proproteins, one or more of the mammalian PCs were anticipated to share structural features with the yeast enzyme 156 . A database search identified a previously reported protein encoded by the FUR ('fes/fps upstream region') locus 157 , an open reading frame adjacent to the fes/fps proto-oncogene, as the first mammalian Kex2 homologue 158 . The product of this genefurin -was soon shown to correctly process precursors for neurotrophic factors, serum proteins and pathogen molecules 6,159,160 .…”

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confidence: 99%

Furin at the cutting edge: From protein traffic to embryogenesis and disease

Thomas

2002

Nat Rev Mol Cell Biol

1,116

1,285

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Furin catalyses a simple biochemical reaction -the proteolytic maturation of proprotein substrates in the secretory pathway. But the simplicity of this reaction belies furin's broad and important roles in homeostasis, as well as in diseases ranging from Alzheimer's disease and cancer to anthrax and Ebola fever. This review summarizes various features of furin -its structural and enzymatic properties, intracellular localization, trafficking, substrates, and roles in vivo.Furin is a cellular ENDOPROTEASE that was identified in 1990 (BOX 1); it proteolytically activates large numbers of PROPROTEIN substrates in secretory pathway compartments. As well as activating pathogenic agents (BOX 2), furin has an essential role in embryogenesis, and catalyses the maturation of a strikingly diverse collection of proprotein substrates. These range from growth factors and receptors to extracellular-matrix proteins and even other protease systems that control disease. Until recently, furin was thought to be an unglamorous housekeeping protein; however, furin's crucial role in so many different cellular events -and in diseases ranging from from anthrax and bird flu (BOX 2) to cancer, dementia and Ebola fever -has caused researchers to re-evaluate it. In this review, I summarize the various features of furin: its structural and enzymatic properties, autoactivation, intracellular localization and trafficking; its substrates; and its roles in vivo, including the requirement for furin in determining the PATHOGENICITY of many viruses and bacteria.

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“…Among the kexins, the first identified was Kex2 (17), which is expressed by Saccharomyces cerevisiae; subsequently, the mammalian kexinlike protease furin was identified (18). Furin processes the precursors of biologically active peptides and proteins via limited proteolysis at paired basic amino acids to generate biologically active molecules (19).…”

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confidence: 99%

Structural Basis for the Kexin-like Serine Protease from Aeromonas sobria as Sepsis-causing Factor

Kobayashi

Utsunomiya

Yamanaka

et al. 2009

Journal of Biological Chemistry

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The anaerobic bacterium Aeromonas sobria is known to cause potentially lethal septic shock. We recently proposed that A. sobria serine protease (ASP) is a sepsis-related factor that induces vascular leakage, reductions in blood pressure via kinin release, and clotting via activation of prothrombin. ASP preferentially cleaves peptide bonds that follow dibasic amino acid residues, as do Kex2 (Saccharomyces cerevisiae serine protease) and furin, which are representative kexin family proteases. Here, we revealed the crystal structure of ASP at 1.65 Å resolution using the multiple isomorphous replacement method with anomalous scattering. Although the overall structure of ASP resembles that of Kex2, it has a unique extra occluding region close to its active site. Moreover, we found that a nicked ASP variant is cleaved within the occluding region. Nicked ASP shows a greater ability to cleave small peptide substrates than the native enzyme. On the other hand, the cleavage pattern for prekallikrein differs from that of ASP, suggesting the occluding region is important for substrate recognition. The extra occluding region of ASP is unique and could serve as a useful target to facilitate development of novel antisepsis drugs.

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Characterization of human c-fes/fps reveals a new transcription unit (fur) in the immediately upstream region of the proto-oncogene

Cited by 92 publications

References 35 publications

Myeloid expression of the human c-fps/fes proto-oncogene in transgenic mice.

Myeloid expression of the human c-fps/fes proto-oncogene in transgenic mice.

Furin at the cutting edge: From protein traffic to embryogenesis and disease

Structural Basis for the Kexin-like Serine Protease from Aeromonas sobria as Sepsis-causing Factor

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