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Gene Review

PCSK5  -  proprotein convertase subtilisin/kexin type 5

Homo sapiens

Synonyms: PC5, PC6, PC6A, Proprotein convertase 5, Proprotein convertase 6, ...
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Disease relevance of PCSK5

  • Isolation of the human PC6 gene encoding the putative host protease for HIV-1 gp160 processing in CD4+ T lymphocytes [1].
  • The data show that the natural gain-of-function mutations R218S, F216L, and D374Y associated with hypercholesterolemia result in total or partial loss of furin/PC5/6A processing at the motif RFHR(218) downward arrow [2].
  • Using a recombinant vaccinia virus-based expression system, PACE4 was expressed in pig kidney PK(15) cells and, like two other Kex2-like endoproteases furin and PC6A, shown to correctly process the precursor of von Willebrand factor (pro-vWF) [3].
  • Here, we use GT1-7 (mouse hypothalamic) and SK-N-MC and SK-N-SH (human neuroblastoma) tumor cell lines to study the ability of PC5 to process pro-CCK [4].
  • Comparable results were also obtained when PC6 was used to inhibit HIV-1 replication in the U937 human histiocytic lymphoma cell line [5].

Psychiatry related information on PCSK5

  • The purpose of this study was to assess the effects of reducing driving fatigue with magnitopuncture stimuli on Dazhui (DU14) point and Neiguan (PC6) points using heart rate (HR), reaction time (RT) testing, right rate (RR), critical flicker fusion frequency (CFF) and subjective evaluation [6].

High impact information on PCSK5

  • Our results suggest that MIS is a natural substrate for PC5, thereby supporting a role for prohormone convertases in the activation of transforming growth factor beta-related hormones during development [7].
  • These kex2/subtilisin-like enzymes, PC5 and furin, are members of the proprotein convertase family that have been implicated in hormone bioactivation via proteolytic processing after dibasic amino acid cleavage recognition sites [7].
  • Two isoforms of the hPC6 protease are expressed in human T cells, hPC6A and the larger hPC6B [1].
  • We have carefully analyzed the expression of PC5 in the mouse during development and in adulthood by in situ hybridization, as well as in mouse tissues and various cell lines by quantitative reverse transcription-PCR [8].
  • The 3-methyl analogue, 8-carbamoyl-3-methylimidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (CCRG 81045), was investigated further and found to possess good activity, when administered i.p., against the L1210 and P388 leukemias, the M5076 reticulum cell sarcoma, B16 melanoma, and ADJ/PC6A plasmacytoma [9].

Chemical compound and disease context of PCSK5

  • This comparison led to the conclusion that the hPC6 gene products are the most likely candidates for the host cell protease responsible for HIV-1 gp160 processing in human CD4+ T cells [1].
  • New rhodium(I) complexes, belonging to the general structure [Rh(CO)2 (L)], where dithiocarbamate and xanthate derivatives, were synthesized and assayed as cytostatic and antitumour agents in vitro against KB cells and in vivo against P388 leukaemia, Ehrlich ascites carcinoma, Sarcoma 180 ascites and ADJ/PC6A solid tumour [10].

Biological context of PCSK5

  • The identification of these amplification primers and SNPs provides tools to investigate PCSK5 for association with inflammatory or vascular phenotypes [11].
  • The human PCSK5 gene, which encodes a subtilisin-like proprotein processing enzyme, has been mapped by analysis of somatic cell hybrids and YAC clones as well as fluorescence in situ hybridization to chromosome 9q21.3 near markers D9S175 and D9S276 [12].
  • The prosegment of the basic-amino acid specific convertases (e.g. furin and PC5) or alpha(1)-PDX, a variant of alpha(1)-antitrypsin (alpha(1)-AT) exhibiting an RIPR(358) sequence at the reactive site loop, were shown to potently inhibit these secretory proteinases [13].
  • The pathogenicity of these strains is related to the presence of a polybasic cleavage sequence in the precursor of the surface glycoprotein haemagglutinin, which makes the glycoprotein susceptible to activation by ubiquitous proteases such as furin and PC6 [14].
  • To determine whether RPTPmu cleavage depended on PC5 (a subtilisin/kexin like endoprotease present in endothelial cells), we transfected COS cells with expression plasmids coding for RPTPmu and PC5 or the closely related protease PACE4 [15].

Anatomical context of PCSK5

  • These results suggest that PC5/6 plays a key role for decidualization in human endometrium [16].
  • The activation of human prorenin by PC5 depended on a pair of basic amino acids at positions 42 and 43 of the prorenin prosegment and occurred only in cells containing dense core secretory granules [17].
  • PC5 mRNA was detected in multiple human tissues, including the brain, adrenal and thyroid glands, heart, placenta, lung, and testes [17].
  • Human PC5 was colocalized with renin by immunohistochemistry in the zona glomerulosa of the adrenal gland, suggesting that it could participate in the activation of a local renin-angiotensin system in the human adrenal cortex [17].
  • The data demonstrate that furin, PC5/6, and the newly cloned PC7 are the main transcribed convertases, suggesting that these proteinases are the major gp160-converting enzymes in T4 lymphocytes [18].

Associations of PCSK5 with chemical compounds

  • Real-time PCR analyses revealed a significant increase in PC5/6 mRNA levels in ESCs treated with 17 beta-estradiol (E(2)) plus medroxy-progesterone acetate during decidualization [16].
  • This PC5/6 immunoreactivity was abolished by cotreatment with ZK 98299, a progesterone receptor antagonist [16].
  • Similarly, PC6A is also able to bind to heparin, whereas soluble furin does not [19].
  • These results suggest that PACE4 and PC6 are unique SPC family proteases that anchor heparan sulfate proteoglycans at the ECM [19].
  • PACE4, furin and PC6 are Ca2+-dependent serine endoproteases that belong to the subtilisin-like proprotein convertase (SPC) family [20].

Other interactions of PCSK5

  • 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 alpha(1) antitrypsin Portland [21].
  • The conclusions drawn from the results of this study may well be applicable to the mammalian convertases PC4, PACE4, and PC5, which also display C-terminal sequence heterogeneity [22].
  • PC5/6 is a member of the PC family responsible for processing precursor proteins to their active forms by selective proteolysis [16].
  • Single-nucleotide polymorphisms of the proprotein convertase subtilisin/ kexin type 5 (PCSK5) gene [11].
  • Pituitary GH3 cells express high levels of PC2 and PC5 [23].

Analytical, diagnostic and therapeutic context of PCSK5

  • Western blotting revealed PC5/6 as approximately 120-kDa bands (pro- and mature forms) and a 65-kDa band (C-terminally truncated form) in decidualized ESCs [16].
  • The PC-isozymes furin and PC5 are expressed in human atherosclerotic lesions and have been found to be up-regulated, following vascular injury in animal models in vivo [24].
  • Functional MRI (fMRI) was used to investigate neural substrates responding to the acupuncture stimulation of Pericardium 6 (PC6, Neiguan), an acupoint relevant for the management of nausea including vestibular-related motion sickness [25].
  • Further studies will assess if acupressure to PC6 can provide a therapeutic or prognostic utility with GMA or GI symptoms in SSc patients [26].
  • EAP (1 Hz, for 30 min) was applied at either ST36, or PC6, or both acupoints in eight healthy volunteers [27].


  1. Isolation of the human PC6 gene encoding the putative host protease for HIV-1 gp160 processing in CD4+ T lymphocytes. Miranda, L., Wolf, J., Pichuantes, S., Duke, R., Franzusoff, A. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  2. The Proprotein Convertase (PC) PCSK9 Is Inactivated by Furin and/or PC5/6A: FUNCTIONAL CONSEQUENCES OF NATURAL MUTATIONS AND POST-TRANSLATIONAL MODIFICATIONS. Benjannet, S., Rhainds, D., Hamelin, J., Nassoury, N., Seidah, N.G. J. Biol. Chem. (2006) [Pubmed]
  3. Proprotein processing activity and cleavage site selectivity of the Kex2-like endoprotease PACE4. Creemers, J.W., Groot Kormelink, P.J., Roebroek, A.J., Nakayama, K., Van de Ven, W.J. FEBS Lett. (1993) [Pubmed]
  4. Neuronal cell lines expressing PC5, but not PC1 or PC2, process Pro-CCK into glycine-extended CCK 12 and 22. Cain, B.M., Vishnuvardhan, D., Beinfeld, M.C. Peptides (2001) [Pubmed]
  5. Modification of human immunodeficiency viral replication by pine cone extracts. Lai, P.K., Donovan, J., Takayama, H., Sakagami, H., Tanaka, A., Konno, K., Nonoyama, M. AIDS Res. Hum. Retroviruses (1990) [Pubmed]
  6. Reducing the effects of driving fatigue with magnitopuncture stimulation. Li, Z., Jiao, K., Chen, M., Wang, C. Accident; analysis and prevention. (2004) [Pubmed]
  7. Bioactivation of Müllerian inhibiting substance during gonadal development by a kex2/subtilisin-like endoprotease. Nachtigal, M.W., Ingraham, H.A. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  8. Deletion of the gene encoding proprotein convertase 5/6 causes early embryonic lethality in the mouse. Essalmani, R., Hamelin, J., Marcinkiewicz, J., Chamberland, A., Mbikay, M., Chrétien, M., Seidah, N.G., Prat, A. Mol. Cell. Biol. (2006) [Pubmed]
  9. Antitumor activity and pharmacokinetics in mice of 8-carbamoyl-3-methyl-imidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (CCRG 81045; M & B 39831), a novel drug with potential as an alternative to dacarbazine. Stevens, M.F., Hickman, J.A., Langdon, S.P., Chubb, D., Vickers, L., Stone, R., Baig, G., Goddard, C., Gibson, N.W., Slack, J.A. Cancer Res. (1987) [Pubmed]
  10. Pharmacological and toxicological studies on new Rh(I) organometallic complexes. Craciunescu, D.G., Scarcia, V., Furlani, A., Papaioannou, A., Parrondo Iglesias, E., Alonso, M.P. In Vivo (1991) [Pubmed]
  11. Single-nucleotide polymorphisms of the proprotein convertase subtilisin/ kexin type 5 (PCSK5) gene. Cao, H., Mok, A., Miskie, B., Hegele, R.A. J. Hum. Genet. (2001) [Pubmed]
  12. Assignment of the human proprotein convertase gene PCSK5 to chromosome 9q21.3. van de Loo, J.W., Creemers, J.W., Kas, K., Roebroek, A.J., Van de Ven, W.J. Cytogenet. Cell Genet. (1996) [Pubmed]
  13. Development of protein-based inhibitors of the proprotein of convertase SKI-1/S1P: processing of SREBP-2, ATF6, and a viral glycoprotein. Pullikotil, P., Vincent, M., Nichol, S.T., Seidah, N.G. J. Biol. Chem. (2004) [Pubmed]
  14. The pathogenesis of influenza in humans. Zambon, M.C. Rev. Med. Virol. (2001) [Pubmed]
  15. Increased proteolytic processing of protein tyrosine phosphatase mu in confluent vascular endothelial cells: the role of PC5, a member of the subtilisin family. Campan, M., Yoshizumi, M., Seidah, N.G., Lee, M.E., Bianchi, C., Haber, E. Biochemistry (1996) [Pubmed]
  16. Requirement for proprotein convertase 5/6 during decidualization of human endometrial stromal cells in vitro. Okada, H., Nie, G., Salamonsen, L.A. J. Clin. Endocrinol. Metab. (2005) [Pubmed]
  17. Prohormone convertase PC5 is a candidate processing enzyme for prorenin in the human adrenal cortex. Mercure, C., Jutras, I., Day, R., Seidah, N.G., Reudelhuber, T.L. Hypertension (1996) [Pubmed]
  18. Identification of the paired basic convertases implicated in HIV gp160 processing based on in vitro assays and expression in CD4(+) cell lines. Decroly, E., Wouters, S., Di Bello, C., Lazure, C., Ruysschaert, J.M., Seidah, N.G. J. Biol. Chem. (1996) [Pubmed]
  19. Secretory proprotein convertases PACE4 and PC6A are heparin-binding proteins which are localized in the extracellular matrix. Potential role of PACE4 in the activation of proproteins in the extracellular matrix. Tsuji, A., Sakurai, K., Kiyokage, E., Yamazaki, T., Koide, S., Toida, K., Ishimura, K., Matsuda, Y. Biochim. Biophys. Acta (2003) [Pubmed]
  20. Development of selectivity of alpha1-antitrypsin variant by mutagenesis in its reactive site loop against proprotein convertase. A crucial role of the P4 arginine in PACE4 inhibition. Tsuji, A., Ikoma, T., Hashimoto, E., Matsuda, Y. Protein Eng. (2002) [Pubmed]
  21. Regulation of membrane type-1 matrix metalloproteinase activation by proprotein convertases. Yana, I., Weiss, S.J. Mol. Biol. Cell (2000) [Pubmed]
  22. Processing specificity and biosynthesis of the Drosophila melanogaster convertases dfurin1, dfurin1-CRR, dfurin1-X, and dfurin2. De Bie, I., Savaria, D., Roebroek, A.J., Day, R., Lazure, C., Van de Ven, W.J., Seidah, N.G. J. Biol. Chem. (1995) [Pubmed]
  23. CCK processing by pituitary GH3 cells, human teratocarcinoma cells NT2 and hNT differentiated human neuronal cells evidence for a differentiation-induced change in enzyme expression and pro CCK processing. Beinfeld, M.C., Wang, W. Life Sci. (2002) [Pubmed]
  24. Proprotein convertases furin and PC5: targeting atherosclerosis and restenosis at multiple levels. Stawowy, P., Fleck, E. J. Mol. Med. (2005) [Pubmed]
  25. Modulation of cerebellar activities by acupuncture stimulation: evidence from fMRI study. Yoo, S.S., Teh, E.K., Blinder, R.A., Jolesz, F.A. Neuroimage (2004) [Pubmed]
  26. Patients with systemic sclerosis have unique and persistent alterations in gastric myoelectrical activity with acupressure to Neiguan point PC6. Wollaston, D.E., Xu, X., Tokumaru, O., Chen, J.D., McNearney, T.A. J. Rheumatol. (2005) [Pubmed]
  27. Effects of electroacupuncture on gastric myoelectrical activity in healthy humans. Shiotani, A., Tatewaki, M., Hoshino, E., Takahashi, T. Neurogastroenterol. Motil. (2004) [Pubmed]
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