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Gene Review

VCP  -  valosin containing protein

Homo sapiens

Synonyms: 15S Mg(2+)-ATPase p97 subunit, ALS14, HEL-220, HEL-S-70, IBMPFD, ...
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Disease relevance of VCP


High impact information on VCP


Chemical compound and disease context of VCP

  • VCP was found to be constitutively phosphorylated on tyrosine in Rous sarcoma virus-transformed fibroblasts [7].
  • PURPOSE: From 1986 to 1992, "eight-drugs-in-one-day" (8-in-1) chemotherapy both before and after radiation therapy (XRT) (54 Gy tumor/36 Gy neuraxis) was compared with vincristine, lomustine (CCNU), and prednisone (VCP) after XRT in children with untreated, high-stage medulloblastoma (MB) [8].
  • Chimeric Envs between HIV-2/vcp and a CD4-dependent clone of HIV-2/NIHz as well as site-directed Env mutations implicated a positively charged amino acid (lysine or arginine) at position 427 in the C4 region of the HIV-2/vcp env gene product (VCP) gp120 as a key determinant for this phenotype [9].
  • p97 is a cell-surface glycoprotein that is present in most human melanomas but only in trace amounts in normal adult tissues [10].
  • This cell surface material released by mild trypsin digestion from galactose-labeled human teratocarcinoma cells, Tera I and PA1, was digested extensively with pronase [11].

Biological context of VCP

  • Although we were unable to determine the exact site of phosphorylation of VCP, we did confirm, using a cross-immunoprecipitation approach, that this protein is tyrosine phosphorylated during capacitation [12].
  • The amplified human fragment served as probe on Southern blots of hybrid DNAs to determine that the human VCP locus maps to chromosome region 9pter-q34 [13].
  • Quantitative reverse transcription polymerase chain reaction analysis showed higher VCP mRNA expression in malignant PENs (n = 5) than benign cases (n = 5) (p < 0.05) [14].
  • A cell-free system that mimics the reassembly of Golgi stacks at the end of mitosis requires two ATPases, NSF and p97, to rebuild Golgi cisternae [15].
  • VCP has been implicated in control of a variety of membrane functions, including membrane fusions, and is a regulator of the cell cycle [16].

Anatomical context of VCP


Associations of VCP with chemical compounds

  • The inhibition of the major stress-inducible transcription factor CHOP (CCAAT/enhancer-binding protein homologous protein)/GADD153 together with bortezomib was most effective in repressing NFkappaB-mediated IL8 activation compared with interference of VCP, MLN-273 (proteasome inhibitor), or 4-phenylbutyrate (histone deacetylase inhibitor) [20].
  • Interference in the VCP-CFTR complex promoted accumulation of immature CFTR in the ER and partial rescue of functional chloride channels to the cell surface [20].
  • Glutathione S-transferase pull-down experiments showed that all three VCP mutations do not affect the binding to Ufd1, Npl4 and ataxin-3 [18].
  • Moreover, induction of wild type PTPH1 resulted in specific dephosphorylation of VCP without changing the overall phosphotyrosine profile of the cells [16].
  • Glycerol gradient centrifugation analysis showed that endogenous Dorfin consisted of a 400-600-kDa complex and was co-immunoprecipitated with endogenous VCP [2].

Physical interactions of VCP

  • How the ubiquitination machinery is recruited to the p97/Derlin/VIMP complex is unclear [21].
  • Ataxin-3 binds VCP/p97 and regulates retrotranslocation of ERAD substrates [22].
  • These results suggest that hFAF1 binding to ubiquitinated protein and VCP is involved in the ubiquitin-proteasome pathway [23].
  • In vitro experiments showed that Dorfin interacted directly with VCP through its C-terminal region [2].
  • The PUB domain functions as a p97 binding module in human peptide N-glycanase [24].

Regulatory relationships of VCP


Other interactions of VCP

  • These findings indicate that Derlin-2 and -3 provide the missing link between EDEM and p97 in the process of degrading misfolded glycoproteins [27].
  • During retrotranslocation, a substrate first interacts with Derlin-1 before p97 and other factors join the complex [21].
  • Human Fas-associated factor 1, interacting with ubiquitinated proteins and valosin-containing protein, is involved in the ubiquitin-proteasome pathway [23].
  • NSF and p97/VCP: similar at first, different at last [28].
  • METHODS: The Ki-67 LI and VCP expression at the mRNA and protein level were evaluated in 32 patients (12 male and 20 female) with PENs aged from 22 to 73 years (median 49 years) [14].

Analytical, diagnostic and therapeutic context of VCP

  • RESULTS: Five cases (15.6%) showed level 1 and 25 (84.4%) level 2 VCP expression by immunohistochemistry [14].
  • To map the human VCP sequence, a human-specific probe was made by RT-PCR of human mRNA using oligonucleotide primers from conserved regions of the porcine sequence [13].
  • VCP level was an indicator for disease-free survival in each early- (I and II) and advanced- (III and IV) stage group of pathologic tumor-node-metastasis classification (P <.001 and P <.01, respectively) [5].
  • A new stringent method of microarray analysis demonstrated that only four transcripts were nonspecifically affected by RNAi, whereas approximately 30 transcripts were affected in response to reduced VCP levels in a sequence-independent manner [29].
  • Sequence analysis of the predicted polypeptide revealed 63 to 66% similarity with S. cerevisiae CDC 48p and its related genes in amphibians (p97ATPase) and mammals (Valosin Containing Protein, VCP), all possibly involved in the regulation of the cell cycle [30].


  1. VCP (p97) regulates NFkappaB signaling pathway, which is important for metastasis of osteosarcoma cell line. Asai, T., Tomita, Y., Nakatsuka, S., Hoshida, Y., Myoui, A., Yoshikawa, H., Aozasa, K. Jpn. J. Cancer Res. (2002) [Pubmed]
  2. Physical and functional interaction between Dorfin and Valosin-containing protein that are colocalized in ubiquitylated inclusions in neurodegenerative disorders. Ishigaki, S., Hishikawa, N., Niwa, J., Iemura, S., Natsume, T., Hori, S., Kakizuka, A., Tanaka, K., Sobue, G. J. Biol. Chem. (2004) [Pubmed]
  3. Valosin-containing protein, VCP, is a ubiquitous clathrin-binding protein. Pleasure, I.T., Black, M.M., Keen, J.H. Nature (1993) [Pubmed]
  4. Mutant valosin-containing protein causes a novel type of frontotemporal dementia. Schröder, R., Watts, G.D., Mehta, S.G., Evert, B.O., Broich, P., Fliessbach, K., Pauls, K., Hans, V.H., Kimonis, V., Thal, D.R. Ann. Neurol. (2005) [Pubmed]
  5. Elevated expression of valosin-containing protein (p97) in hepatocellular carcinoma is correlated with increased incidence of tumor recurrence. Yamamoto, S., Tomita, Y., Nakamori, S., Hoshida, Y., Nagano, H., Dono, K., Umeshita, K., Sakon, M., Monden, M., Aozasa, K. J. Clin. Oncol. (2003) [Pubmed]
  6. Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein. Watts, G.D., Wymer, J., Kovach, M.J., Mehta, S.G., Mumm, S., Darvish, D., Pestronk, A., Whyte, M.P., Kimonis, V.E. Nat. Genet. (2004) [Pubmed]
  7. Tyrosine phosphorylation of VCP, the mammalian homologue of the Saccharomyces cerevisiae CDC48 protein, is unusually sensitive to stimulation by sodium vanadate and hydrogen peroxide. Schulte, R.J., Campbell, M.A., Fischer, W.H., Sefton, B.M. J. Immunol. (1994) [Pubmed]
  8. Metastasis stage, adjuvant treatment, and residual tumor are prognostic factors for medulloblastoma in children: conclusions from the Children's Cancer Group 921 randomized phase III study. Zeltzer, P.M., Boyett, J.M., Finlay, J.L., Albright, A.L., Rorke, L.B., Milstein, J.M., Allen, J.C., Stevens, K.R., Stanley, P., Li, H., Wisoff, J.H., Geyer, J.R., McGuire-Cullen, P., Stehbens, J.A., Shurin, S.B., Packer, R.J. J. Clin. Oncol. (1999) [Pubmed]
  9. CD4-independent use of Rhesus CCR5 by human immunodeficiency virus Type 2 implicates an electrostatic interaction between the CCR5 N terminus and the gp120 C4 domain. Lin, G., Lee, B., Haggarty, B.S., Doms, R.W., Hoxie, J.A. J. Virol. (2001) [Pubmed]
  10. Primary structure of the human melanoma-associated antigen p97 (melanotransferrin) deduced from the mRNA sequence. Rose, T.M., Plowman, G.D., Teplow, D.B., Dreyer, W.J., Hellström, K.E., Brown, J.P. Proc. Natl. Acad. Sci. U.S.A. (1986) [Pubmed]
  11. Biochemical properties of the high-molecular-weight glycopeptides released from the cell surface of human teratocarcinoma cells. Muramatsu, H., Muramatsu, T., Avner, P. Cancer Res. (1982) [Pubmed]
  12. Phosphoproteome analysis of capacitated human sperm. Evidence of tyrosine phosphorylation of a kinase-anchoring protein 3 and valosin-containing protein/p97 during capacitation. Ficarro, S., Chertihin, O., Westbrook, V.A., White, F., Jayes, F., Kalab, P., Marto, J.A., Shabanowitz, J., Herr, J.C., Hunt, D.F., Visconti, P.E. J. Biol. Chem. (2003) [Pubmed]
  13. Chromosome localization of human genes for clathrin adaptor polypeptides AP2 beta and AP50 and the clathrin-binding protein, VCP. Druck, T., Gu, Y., Prabhala, G., Cannizzaro, L.A., Park, S.H., Huebner, K., Keen, J.H. Genomics (1995) [Pubmed]
  14. Valosin-containing protein (p97) and Ki-67 expression is a useful marker in detecting malignant behavior of pancreatic endocrine neoplasms. Yamamoto, S., Tomita, Y., Nakamori, S., Hoshida, Y., Iizuka, N., Okami, J., Nagano, H., Dono, K., Umeshita, K., Sakon, M., Ishikawa, O., Ohigashi, H., Aozasa, K., Monden, M. Oncology (2004) [Pubmed]
  15. Syntaxin 5 is a common component of the NSF- and p97-mediated reassembly pathways of Golgi cisternae from mitotic Golgi fragments in vitro. Rabouille, C., Kondo, H., Newman, R., Hui, N., Freemont, P., Warren, G. Cell (1998) [Pubmed]
  16. Identification of the cell cycle regulator VCP (p97/CDC48) as a substrate of the band 4.1-related protein-tyrosine phosphatase PTPH1. Zhang, S.H., Liu, J., Kobayashi, R., Tonks, N.K. J. Biol. Chem. (1999) [Pubmed]
  17. Yeast two-hybrid screening identifies binding partners of human Tom34 that have ATPase activity and form a complex with Tom34 in the cytosol. Yang, C.S., Weiner, H. Arch. Biochem. Biophys. (2002) [Pubmed]
  18. Pathological consequences of VCP mutations on human striated muscle. Hübbers, C.U., Clemen, C.S., Kesper, K., Böddrich, A., Hofmann, A., Kämäräinen, O., Tolksdorf, K., Stumpf, M., Reichelt, J., Roth, U., Krause, S., Watts, G., Kimonis, V., Wattjes, M.P., Reimann, J., Thal, D.R., Biermann, K., Evert, B.O., Lochmüller, H., Wanker, E.E., Schoser, B.G., Noegel, A.A., Schröder, R. Brain (2007) [Pubmed]
  19. Functional ATPase activity of p97/valosin-containing protein (VCP) is required for the quality control of endoplasmic reticulum in neuronally differentiated mammalian PC12 cells. Kobayashi, T., Tanaka, K., Inoue, K., Kakizuka, A. J. Biol. Chem. (2002) [Pubmed]
  20. Selective inhibition of endoplasmic reticulum-associated degradation rescues DeltaF508-cystic fibrosis transmembrane regulator and suppresses interleukin-8 levels: therapeutic implications. Vij, N., Fang, S., Zeitlin, P.L. J. Biol. Chem. (2006) [Pubmed]
  21. Inaugural Article: Recruitment of the p97 ATPase and ubiquitin ligases to the site of retrotranslocation at the endoplasmic reticulum membrane. Ye, Y., Shibata, Y., Kikkert, M., van Voorden, S., Wiertz, E., Rapoport, T.A. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  22. Ataxin-3 binds VCP/p97 and regulates retrotranslocation of ERAD substrates. Zhong, X., Pittman, R.N. Hum. Mol. Genet. (2006) [Pubmed]
  23. Human Fas-associated factor 1, interacting with ubiquitinated proteins and valosin-containing protein, is involved in the ubiquitin-proteasome pathway. Song, E.J., Yim, S.H., Kim, E., Kim, N.S., Lee, K.J. Mol. Cell. Biol. (2005) [Pubmed]
  24. The PUB domain functions as a p97 binding module in human peptide N-glycanase. Allen, M.D., Buchberger, A., Bycroft, M. J. Biol. Chem. (2006) [Pubmed]
  25. An arginine/lysine-rich motif is crucial for VCP/p97-mediated modulation of ataxin-3 fibrillogenesis. Boeddrich, A., Gaumer, S., Haacke, A., Tzvetkov, N., Albrecht, M., Evert, B.O., Müller, E.C., Lurz, R., Breuer, P., Schugardt, N., Plassmann, S., Xu, K., Warrick, J.M., Suopanki, J., Wüllner, U., Frank, R., Hartl, U.F., Bonini, N.M., Wanker, E.E. EMBO J. (2006) [Pubmed]
  26. Pre-B-cell leukemia transcription factor 1 regulates expression of valosin-containing protein, a gene involved in cancer growth. Qiu, Y., Tomita, Y., Zhang, B., Nakamichi, I., Morii, E., Aozasa, K. Am. J. Pathol. (2007) [Pubmed]
  27. Derlin-2 and Derlin-3 are regulated by the mammalian unfolded protein response and are required for ER-associated degradation. Oda, Y., Okada, T., Yoshida, H., Kaufman, R.J., Nagata, K., Mori, K. J. Cell Biol. (2006) [Pubmed]
  28. NSF and p97/VCP: similar at first, different at last. Brunger, A.T., DeLaBarre, B. FEBS Lett. (2003) [Pubmed]
  29. Valosin-containing Protein (p97) Is a Regulator of Endoplasmic Reticulum Stress and of the Degradation of N-End Rule and Ubiquitin-Fusion Degradation Pathway Substrates in Mammalian Cells. W??jcik, C., Rowicka, M., Kudlicki, A., Nowis, D., McConnell, E., Kujawa, M., Demartino, G.N. Mol. Biol. Cell (2006) [Pubmed]
  30. SAV, an archaebacterial gene with extensive homology to a family of highly conserved eukaryotic ATPases. Confalonieri, F., Marsault, J., Duguet, M. J. Mol. Biol. (1994) [Pubmed]
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