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Pcsk1  -  proprotein convertase subtilisin/kexin type 1

Mus musculus

Synonyms: Att-1, Furin homolog, NEC 1, Nec-1, Nec1, ...
 
 
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Disease relevance of Pcsk1

 

Psychiatry related information on Pcsk1

 

High impact information on Pcsk1

  • These data suggest that PC1 and PC2 contribute to fluid-flow sensation by the primary cilium in renal epithelium and that they both function in the same mechanotransduction pathway [7].
  • Cells isolated from transgenic mice that lack functional PC1 formed cilia but did not increase Ca(2+) influx in response to physiological fluid flow [7].
  • Loss or dysfunction of PC1 or PC2 may therefore lead to PKD owing to the inability of cells to sense mechanical cues that normally regulate tissue morphogenesis [7].
  • Endoproteolytic maturation of these proteins is probably mediated by the proprotein convertase SPC1/Furin [8].
  • Inhibition of Id2 expression by RNA interference corrects the hyperproliferative phenotype of PC1 mutant cells [9].
 

Chemical compound and disease context of Pcsk1

 

Biological context of Pcsk1

  • Tissue distribution studies indicate that both PC2 and PC3 are expressed in a variety of neuroendocrine tissues, including pancreatic islets and brain, but are not expressed in liver, kidney, skeletal muscle, and spleen [14].
  • By using different neuroendocrine cell lines, with or without endogenous expression of either PC2 or PC1/3 or both enzymes, we have demonstrated through transient transfection studies that long pro-CART gives rise to an intermediate peptide, residues 33-102, and the two major bioactive CART forms, residues 55-102 (I) and 62-102 (II), respectively [15].
  • Furthermore, the identification of the NEC1 locus on human chromosome 5 and mouse chromosome 13 suggests a conservation of synthenic regions between these regions of the human and mouse genomes [16].
  • The genes for PC1 and PC2 were located on human chromosomes 5q15-21 and 20p11.1-11.2, respectively [16].
  • The presence of severe obesity and the absence of growth retardation in both subjects contrast markedly with the phenotype of mice lacking PC1 and suggest that the precise physiological repertoire of this enzyme may vary between mammalian species [5].
 

Anatomical context of Pcsk1

  • We have used the polymerase chain reaction to identify and clone a cDNA (PC3) from the mouse AtT20 anterior pituitary cell line that represents an additional member of this growing family of mammalian proteases [14].
  • The neuroendocrine processing endoproteases PC2 and PC1/3 are expressed in the beta cells of the islets of Langerhans and participate in the processing of proinsulin to insulin and C-peptide [17].
  • Our data demonstrated that both PC1 and PC2 transcripts can be detected in the presumptive adenohypophysis starting on embryonic day 15 (E15) [18].
  • Ontogeny of the prohormone convertases PC1 and PC2 in the mouse hypophysis and their colocalization with corticotropin and alpha-melanotropin [18].
  • In contrast, GH4C1 and COS 7 cells, which express very little or no PC2 or PC3, failed to process proglucagon, aside from a low level of interdomain cleavage which occurred only in the GH4C1 cells [19].
 

Associations of Pcsk1 with chemical compounds

  • These data indicate that PC2 is essential for processing of proIAPP at the NH2-terminal cleavage site in vivo and that PC3 is likely only capable of processing proIAPP at the COOH-terminal cleavage site [20].
  • We conclude that PC1/3 is important for processing of proIAPP at the COOH-terminus, but in its absence, PC2 can initiate complete processing of proIAPP to IAPP by cleaving the precursor at either its NH(2)- or COOH-terminal cleavage sites [21].
  • The removal of Ca(2+) with chelating agents partially releases the bound PC1 [22].
  • Biological processing of the cocaine and amphetamine-regulated transcript precursors by prohormone convertases, PC2 and PC1/3 [15].
  • PC2 cleaved proDyn to produce dynorphin (Dyn) A 1-17, Dyn B 1-13, and alpha-neo-endorphin, without a previous requirement for PC1/PC3 [23].
 

Physical interactions of Pcsk1

  • We previously showed that the neuroendocrine polypeptide 7B2 transiently interacts with prohormone convertase PC2 in the secretory pathway of neuroendocrine cells [24].
 

Enzymatic interactions of Pcsk1

  • Recombinant PC1 was also found to cleave ACTH to ACTH-(1-15) and bovine N-POMC-(1-77) to gamma 3 MSH [25].
  • 3) PC2 was much weaker in cleaving the C-terminal site relative to PC1/3 to generate mature GHRH [26].
  • PC3 generates mature insulin but cleaves preferentially at the proinsulin B-chain-C-peptide junction [27].
 

Co-localisations of Pcsk1

 

Regulatory relationships of Pcsk1

  • Antisense PC1 specifically abolished regulated secretion of both chromogranin A and beta-endorphin in response to the usual secretagogue, corticotropin-releasing hormone [29].
  • Recently, the prohormone convertase SPC-6 has been found to be co-expressed in embryo-proximal decidua in association with TIMP-3 [30].
  • These results indicate that the basic pair and the RXK/RR sequence are the signals for precursor cleavages catalyzed by PC3 within the regulated secretory pathway and by furin within the constitutive pathway, respectively [31].
  • Wild-type (WT) and mutant PC1 were stably expressed in neuroendocrine PC12 cells that lacked endogenous PC1 [32].
  • Taken together, these results are consistent with a role for proSAAS-derived peptides as neuropeptides that influence body weight independently of their function as inhibitors of prohormone convertase 1 [33].
  • Similar results were obtained after co-expression of preproGIP and PC1/3 in GH4 cells that express no PC2 and only low levels of PC1/3 [34].
  • These data confirm Nhlh2 as an integral element of the Janus kinase/STAT signaling pathway and are the first to demonstrate coordinated control of PC1/3 transcription by Nhlh2 and STAT3 after leptin stimulation [35].
 

Other interactions of Pcsk1

  • In the intermediate lobe, PC1 and PC2 mRNAs appear on E18 and E16, respectively, and their levels increased during ontogeny, reaching maximal expression in the adult [18].
  • Furthermore, the demonstrated variation in the relative ratio of PC1/PC2 expression during ontogeny rationalizes the observed plasticity of POMC processing in the adenohypophysis [18].
  • Neither PC1 nor PC2 processed glucagon from proglucagon in vitro [36].
  • These islets contained not only fully processed IAPP as in PC1/3(+/+) islets, but also elevated levels of a COOH-terminally unprocessed intermediate form, suggesting impaired processing at the COOH-terminus [21].
  • 2) Both PC1/3 and PC5/6A also processed the N-terminal site but less efficiently than furin [26].
 

Analytical, diagnostic and therapeutic context of Pcsk1

  • The distribution of PC1 and PC2 immunoreactivity is nicely correlated with the in situ hybridization data [18].
  • On Northern blots, PC3 hybridizes to two transcripts of 3 and 5 kilobases [14].
  • To determine whether PC2 might be essential for proIAPP processing, we performed Western blot analysis of freshly isolated islets from normal mice and mice lacking active PC2 [20].
  • To look at the role PC1 plays in neuropeptide processing in brain and pituitary, we used radioimmunoassays (RIA) as well as quantitative peptidomic methods and examined changes in the levels of multiple neuropeptide products in PC1 knockout (KO) mice [37].
  • In order to gain insight into the function of proSAAS, we have examined the distribution of several proSAAS-derived peptides and PC1 by immunohistochemistry throughout mouse development [38].

References

  1. Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. Jackson, R.S., Creemers, J.W., Ohagi, S., Raffin-Sanson, M.L., Sanders, L., Montague, C.T., Hutton, J.C., O'Rahilly, S. Nat. Genet. (1997) [Pubmed]
  2. Disruption of PC1/3 expression in mice causes dwarfism and multiple neuroendocrine peptide processing defects. Zhu, X., Zhou, A., Dey, A., Norrbom, C., Carroll, R., Zhang, C., Laurent, V., Lindberg, I., Ugleholdt, R., Holst, J.J., Steiner, D.F. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  3. Proneuropeptide Y processing in large dense-core vesicles: manipulation of prohormone convertase expression in sympathetic neurons using adenoviruses. Paquet, L., Massie, B., Mains, R.E. J. Neurosci. (1996) [Pubmed]
  4. Impaired prohormone convertases in Cpe(fat)/Cpe(fat) mice. Berman, Y., Mzhavia, N., Polonskaia, A., Devi, L.A. J. Biol. Chem. (2001) [Pubmed]
  5. Small-intestinal dysfunction accompanies the complex endocrinopathy of human proprotein convertase 1 deficiency. Jackson, R.S., Creemers, J.W., Farooqi, I.S., Raffin-Sanson, M.L., Varro, A., Dockray, G.J., Holst, J.J., Brubaker, P.L., Corvol, P., Polonsky, K.S., Ostrega, D., Becker, K.L., Bertagna, X., Hutton, J.C., White, A., Dattani, M.T., Hussain, K., Middleton, S.J., Nicole, T.M., Milla, P.J., Lindley, K.J., O'Rahilly, S. J. Clin. Invest. (2003) [Pubmed]
  6. The proprotein convertase PC2 is involved in the maturation of prosomatostatin to somatostatin-14 but not in the somatostatin deficit in Alzheimer's disease. Winsky-Sommerer, R., Grouselle, D., Rougeot, C., Laurent, V., David, J.P., Delacourte, A., Dournaud, P., Seidah, N.G., Lindberg, I., Trottier, S., Epelbaum, J. Neuroscience (2003) [Pubmed]
  7. Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nauli, S.M., Alenghat, F.J., Luo, Y., Williams, E., Vassilev, P., Li, X., Elia, A.E., Lu, W., Brown, E.M., Quinn, S.J., Ingber, D.E., Zhou, J. Nat. Genet. (2003) [Pubmed]
  8. SPC4/PACE4 regulates a TGFbeta signaling network during axis formation. Constam, D.B., Robertson, E.J. Genes Dev. (2000) [Pubmed]
  9. Polycystin-1 and polycystin-2 regulate the cell cycle through the helix-loop-helix inhibitor Id2. Li, X., Luo, Y., Starremans, P.G., McNamara, C.A., Pei, Y., Zhou, J. Nat. Cell Biol. (2005) [Pubmed]
  10. HIV-1 protease inhibitor, ritonavir: a potent inhibitor of CYP3A4, enhanced the anticancer effects of docetaxel in androgen-independent prostate cancer cells in vitro and in vivo. Ikezoe, T., Hisatake, Y., Takeuchi, T., Ohtsuki, Y., Yang, Y., Said, J.W., Taguchi, H., Koeffler, H.P. Cancer Res. (2004) [Pubmed]
  11. The human immunodeficiency virus (HIV)-1 protease inhibitor saquinavir inhibits proteasome function and causes apoptosis and radiosensitization in non-HIV-associated human cancer cells. Pajonk, F., Himmelsbach, J., Riess, K., Sommer, A., McBride, W.H. Cancer Res. (2002) [Pubmed]
  12. Matrix vesicle plasma cell membrane glycoprotein-1 regulates mineralization by murine osteoblastic MC3T3 cells. Johnson, K., Moffa, A., Chen, Y., Pritzker, K., Goding, J., Terkeltaub, R. J. Bone Miner. Res. (1999) [Pubmed]
  13. In vivo and in vitro effect of baicalein on human prostate cancer cells. Miocinovic, R., McCabe, N.P., Keck, R.W., Jankun, J., Hampton, J.A., Selman, S.H. Int. J. Oncol. (2005) [Pubmed]
  14. Identification of a cDNA encoding a second putative prohormone convertase related to PC2 in AtT20 cells and islets of Langerhans. Smeekens, S.P., Avruch, A.S., LaMendola, J., Chan, S.J., Steiner, D.F. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  15. Biological processing of the cocaine and amphetamine-regulated transcript precursors by prohormone convertases, PC2 and PC1/3. Dey, A., Xhu, X., Carroll, R., Turck, C.W., Stein, J., Steiner, D.F. J. Biol. Chem. (2003) [Pubmed]
  16. Chromosomal assignments of the genes for neuroendocrine convertase PC1 (NEC1) to human 5q15-21, neuroendocrine convertase PC2 (NEC2) to human 20p11.1-11.2, and furin (mouse 7[D1-E2] region). Seidah, N.G., Mattei, M.G., Gaspar, L., Benjannet, S., Mbikay, M., Chrétien, M. Genomics (1991) [Pubmed]
  17. Severe block in processing of proinsulin to insulin accompanied by elevation of des-64,65 proinsulin intermediates in islets of mice lacking prohormone convertase 1/3. Zhu, X., Orci, L., Carroll, R., Norrbom, C., Ravazzola, M., Steiner, D.F. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  18. Ontogeny of the prohormone convertases PC1 and PC2 in the mouse hypophysis and their colocalization with corticotropin and alpha-melanotropin. Marcinkiewicz, M., Day, R., Seidah, N.G., Chrétien, M. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  19. Differential processing of proglucagon by the subtilisin-like prohormone convertases PC2 and PC3 to generate either glucagon or glucagon-like peptide. Rouillé, Y., Martin, S., Steiner, D.F. J. Biol. Chem. (1995) [Pubmed]
  20. The prohormone convertase enzyme 2 (PC2) is essential for processing pro-islet amyloid polypeptide at the NH2-terminal cleavage site. Wang, J., Xu, J., Finnerty, J., Furuta, M., Steiner, D.F., Verchere, C.B. Diabetes (2001) [Pubmed]
  21. Role of beta-cell prohormone convertase (PC)1/3 in processing of pro-islet amyloid polypeptide. Marzban, L., Trigo-Gonzalez, G., Zhu, X., Rhodes, C.J., Halban, P.A., Steiner, D.F., Verchere, C.B. Diabetes (2004) [Pubmed]
  22. The C-terminal region of proSAAS is a potent inhibitor of prohormone convertase 1. Qian, Y., Devi, L.A., Mzhavia, N., Munzer, S., Seidah, N.G., Fricker, L.D. J. Biol. Chem. (2000) [Pubmed]
  23. Prodynorphin processing by proprotein convertase 2. Cleavage at single basic residues and enhanced processing in the presence of carboxypeptidase activity. Day, R., Lazure, C., Basak, A., Boudreault, A., Limperis, P., Dong, W., Lindberg, I. J. Biol. Chem. (1998) [Pubmed]
  24. The neuroendocrine chaperone 7B2 can enhance in vitro POMC cleavage by prohormone convertase PC2. Braks, J.A., Martens, G.J. FEBS Lett. (1995) [Pubmed]
  25. In vitro processing of proopiomelanocortin by recombinant PC1 (SPC3). Friedman, T.C., Loh, Y.P., Birch, N.P. Endocrinology (1994) [Pubmed]
  26. Furin and prohormone convertase 1/3 are major convertases in the processing of mouse pro-growth hormone-releasing hormone. Dey, A., Norrbom, C., Zhu, X., Stein, J., Zhang, C., Ueda, K., Steiner, D.F. Endocrinology (2004) [Pubmed]
  27. Proinsulin processing by the subtilisin-related proprotein convertases furin, PC2, and PC3. Smeekens, S.P., Montag, A.G., Thomas, G., Albiges-Rizo, C., Carroll, R., Benig, M., Phillips, L.A., Martin, S., Ohagi, S., Gardner, P. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  28. Distribution of proSAAS-derived peptides in rat neuroendocrine tissues. Feng, Y., Reznik, S.E., Fricker, L.D. Neuroscience (2001) [Pubmed]
  29. Chromogranin A processing and secretion: specific role of endogenous and exogenous prohormone convertases in the regulated secretory pathway. Eskeland, N.L., Zhou, A., Dinh, T.Q., Wu, H., Parmer, R.J., Mains, R.E., O'Connor, D.T. J. Clin. Invest. (1996) [Pubmed]
  30. Subtilisin proprotein convertase-6 expression in the mouse uterus during implantation and artificially induced decidualization. Wong, B.S., Liu, S., Schultz, G.A., Rancourt, D.E. Mol. Reprod. Dev. (2002) [Pubmed]
  31. Arg-X-Lys/Arg-Arg motif as a signal for precursor cleavage catalyzed by furin within the constitutive secretory pathway. Hosaka, M., Nagahama, M., Kim, W.S., Watanabe, T., Hatsuzawa, K., Ikemizu, J., Murakami, K., Nakayama, K. J. Biol. Chem. (1991) [Pubmed]
  32. The Arg617-Arg618 cleavage site in the C-terminal domain of PC1 plays a major role in the processing and targeting of the enzyme within the regulated secretory pathway. Bernard, N., Kitabgi, P., Rovere-Jovene, C. J. Neurochem. (2003) [Pubmed]
  33. Obesity and diabetes in transgenic mice expressing proSAAS. Wei, S., Feng, Y., Che, F.Y., Pan, H., Mzhavia, N., Devi, L.A., McKinzie, A.A., Levin, N., Richards, W.G., Fricker, L.D. J. Endocrinol. (2004) [Pubmed]
  34. Prohormone convertase 1/3 is essential for processing of the glucose-dependent insulinotropic polypeptide precursor. Ugleholdt, R., Poulsen, M.L., Holst, P.J., Irminger, J.C., Orskov, C., Pedersen, J., Rosenkilde, M.M., Zhu, X., Steiner, D.F., Holst, J.J. J. Biol. Chem. (2006) [Pubmed]
  35. Nescient helix-loop-helix 2 interacts with signal transducer and activator of transcription 3 to regulate transcription of prohormone convertase 1/3. Fox, D.L., Good, D.J. Mol. Endocrinol. (2008) [Pubmed]
  36. Processing of mouse proglucagon by recombinant prohormone convertase 1 and immunopurified prohormone convertase 2 in vitro. Rothenberg, M.E., Eilertson, C.D., Klein, K., Zhou, Y., Lindberg, I., McDonald, J.K., Mackin, R.B., Noe, B.D. J. Biol. Chem. (1995) [Pubmed]
  37. Neuropeptide processing profile in mice lacking prohormone convertase-1. Pan, H., Nanno, D., Che, F.Y., Zhu, X., Salton, S.R., Steiner, D.F., Fricker, L.D., Devi, L.A. Biochemistry (2005) [Pubmed]
  38. ProSAAS and prohormone convertase 1 are broadly expressed during mouse development. Feng, Y., Reznik, S.E., Fricker, L.D. Brain Res. Gene Expr. Patterns (2002) [Pubmed]
 
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