Blood vessel epicardial substance

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Blood vessel epicardial substance
External IDs OMIM604577 MGI1346013 HomoloGene48497 GeneCards: BVES Gene
Species Human Mouse
Entrez 11149 23828
Ensembl ENSG00000112276 ENSMUSG00000071317
UniProt Q8NE79 Q9ES83
RefSeq (mRNA) NM_001199563 NM_024285
RefSeq (protein) NP_001186492 NP_077247
Location (UCSC) Chr 6:
105.54 – 105.59 Mb
Chr 10:
45.34 – 45.37 Mb
PubMed search [1] [2]

Blood vessel epicardial substance (BVES) also known as popeye domain-containing protein 1 (POPDC1) is a protein that in humans is encoded by the BVES gene.[1][2]

Bves is a highly conserved, transmembrane protein that is involved in cell adhesion, cell motility, and most recently has been shown to play a role in vesicular transport.[3][4][5][6] Bves is found in a wide variety of organisms (from flies to humans) and is a member of the evolutionarily conserved Popdc family of proteins. Although the precise molecular function of Bves is unknown, disruption of this protein results in developmental defects and impaired cellular processes fundamental to living organisms.[7][8][9]


Bves was discovered simultaneously by two independent labs in 1999 (Bves was also named Popdc1 at the time of discovery; the current accepted convention is Bves).[2][10] Although initially isolated from cardiac tissue, it was later revealed that Bves is highly expressed in muscle, epithelial and brain tissue.[4] Most studies have focused on determining the function of Bves in epithelial tissue at the cellular level.

Gene family[edit]

Bves is the most studied member of the Popeye domain containing (Popdc) family of genes. The two other members of this family are Popdc2 and Popdc3. Popdc2 and Popdc3 are only found in higher vertebrates and share 50% of their DNA sequence, whereas Bves is only 25% homologous with the evolutionary younger Popdc family members. All three members of the Popdc family contain the highly conserved Popeye domain as the family was named for this specific protein motif.[3][4][5]


Bves is a three-pass transmembrane protein with a short extracellular N-terminus (~40aa) and a larger intracellular C-terminus (~250aa).[11] Within the C-terminus is the Popeye domain, which has been postulated to be important for Bves function. The Popeye domain shares no homology with any known protein motifs, and specific function of this domain is currently unknown, although it is highly conserved across species. Bves exists as a homodimer in vivo, and homodimerization has been shown to be important for function.[12]


Bves is expressed in muscle, epithelial and brain tissue, and is thus found in many adult organs.[5] During development, Bves is detected in all three germ layers and later localizes to the aforementioned tissues.[13] Subcellular localization is present at the plasma membrane and is also seen in punctate, intracellular vesicles. Bves demonstrates dynamic localization, dependent upon cell-cell junction formation. Prior to cell-cell contact, Bves is localized mostly to intracellular vesicles, but as cells begin to form associations, Bves is also present at points of cell-cell contact.[7]

Interacting proteins[edit]

Bves interacts with GEFT, a protein that modulates Rho GTPases, Rac1 and Cdc42, which are important for cell motility through modulation of the actin cytoskeleton.[9] Bves also interacts with VAMP3, a SNARE protein important for vesicle fusion.[6] Additionally, Bves has been shown to interact with the tight junction protein, ZO1, although this interaction is most likely via a protein complex, as a direct physical interaction has never been demonstrated.[7]


Disruption of Bves results in a wide range of cellular and developmental phenotypes. Grossly, cell motility and cell adhesion are impaired. Only recently have the molecular mechanisms underlying the function of Bves been uncovered.

Bves modulates Rho GTPases through interaction with GEFT[edit]

Bves has been shown to interact and co-localize with GEFT, a modulator of Rho GTPase signaling cascades. Disruption of Bves results in decreased cell speed and increased cell roundness, which are cell processes modulated by the Rho GTPases, Rac1 and Cdc42. Accordingly, Bves disruption results in decreased active Rac1 and Cdc42. Taken together, these data demonstrate that Bves modulates Rho GTPase signaling cascades through interaction with GEFT to affect cell movement and morphology.[9]

Bves regulates vesicular transport via interaction with VAMP3[edit]

Bves has been shown to interact with VAMP3, a member of the SNARE complex that facilitates vesicle fusion. VAMP3 is important for recycling of integrins during cell migration and is also necessary for exocytosis of transferrin.[14][15][16][17][18] Upon Bves disruption, cell rounding is increased, a phenotype indicative of decreased adhesion and disruption of integrin function. Accordingly, Bves disruption results in impaired integrin recycling, phenocopying the result seen with inhibition of VAMP3. Similarly, disruption of either Bves results in impaired transferrin recycling again, mimicking the result seen with disruption of VAMP3. Thus, Bves is important for VAMP3-mediated vesicular transport underlying cell migration and transferrin recycling.[6]

Bves is silenced by promoter hypermethylation in malignancy[edit]

Bves is underexpressed in colon, lung, and breast cancer. In colon cancer this occurs very early during tumorigenesis, with Bves underexpression first noted in premalignant adenomas.


  1. ^ Reese DE, Bader DM (September 1999). "Cloning and expression of hbves, a novel and highly conserved mRNA expressed in the developing and adult heart and skeletal muscle in the human". Mamm. Genome 10 (9): 913–5. doi:10.1007/s003359901113. PMID 10441744. 
  2. ^ a b Andrée B, Hillemann T, Kessler-Icekson G, Schmitt-John T, Jockusch H, Arnold HH, Brand T (July 2000). "Isolation and characterization of the novel popeye gene family expressed in skeletal muscle and heart". Dev. Biol. 223 (2): 371–82. doi:10.1006/dbio.2000.9751. PMID 10882522. 
  3. ^ a b Brand T (2005). "The Popeye domain-containing gene family". Cell Biochem. Biophys. 43 (1): 95–103. doi:10.1385/CBB:43:1:095. PMID 16043887. 
  4. ^ a b c Osler ME, Smith TK, Bader DM (March 2006). "Bves, a member of the Popeye domain-containing gene family". Dev. Dyn. 235 (3): 586–93. doi:10.1002/dvdy.20688. PMC 2849751. PMID 16444674. 
  5. ^ a b c Hager HA, Bader DM (June 2009). "Bves: ten years after". Histol. Histopathol. 24 (6): 777–87. PMC 2853719. PMID 19337975. 
  6. ^ a b c Hager HA, Roberts RJ, Cross EE, Proux-Gillardeaux V, Bader DM (February 2010). "Identification of a novel Bves function: regulation of vesicular transport". EMBO J. 29 (3): 532–45. doi:10.1038/emboj.2009.379. PMC 2830705. PMID 20057356. 
  7. ^ a b c Osler ME, Chang MS, Bader DM (October 2005). "Bves modulates epithelial integrity through an interaction at the tight junction". J. Cell. Sci. 118 (Pt 20): 4667–78. doi:10.1242/jcs.02588. PMID 16188940. 
  8. ^ Ripley AN, Osler ME, Wright CV, Bader D (January 2006). "Xbves is a regulator of epithelial movement during early Xenopus laevis development". Proc. Natl. Acad. Sci. U.S.A. 103 (3): 614–9. doi:10.1073/pnas.0506095103. PMC 1334639. PMID 16407138. 
  9. ^ a b c Smith TK, Hager HA, Francis R, Kilkenny DM, Lo CW, Bader DM (June 2008). "Bves directly interacts with GEFT, and controls cell shape and movement through regulation of Rac1/Cdc42 activity". Proc. Natl. Acad. Sci. U.S.A. 105 (24): 8298–303. doi:10.1073/pnas.0802345105. PMC 2423412. PMID 18541910. 
  10. ^ Reese DE, Zavaljevski M, Streiff NL, Bader D (May 1999). "bves: A novel gene expressed during coronary blood vessel development". Dev. Biol. 209 (1): 159–71. doi:10.1006/dbio.1999.9246. PMID 10208750. 
  11. ^ Knight RF, Bader DM, Backstrom JR (August 2003). "Membrane topology of Bves/Pop1A, a cell adhesion molecule that displays dynamic changes in cellular distribution during development". J. Biol. Chem. 278 (35): 32872–9. doi:10.1074/jbc.M301961200. PMID 12815060. 
  12. ^ Kawaguchi M, Hager HA, Wada A, Koyama T, Chang MS, Bader DM (2008). "Identification of a novel intracellular interaction domain essential for Bves function". PLoS ONE 3 (5): e2261. doi:10.1371/journal.pone.0002261. PMC 2373926. PMID 18493308.  open access publication - free to read
  13. ^ Osler ME, Bader DM (March 2004). "Bves expression during avian embryogenesis". Dev. Dyn. 229 (3): 658–67. doi:10.1002/dvdy.10490. PMID 14991721. 
  14. ^ McMahon HT, Ushkaryov YA, Edelmann L, Link E, Binz T, Niemann H, Jahn R, Südhof TC (July 1993). "Cellubrevin is a ubiquitous tetanus-toxin substrate homologous to a putative synaptic vesicle fusion protein". Nature 364 (6435): 346–9. doi:10.1038/364346a0. PMID 8332193. 
  15. ^ Proux-Gillardeaux V, Gavard J, Irinopoulou T, Mège RM, Galli T (May 2005). "Tetanus neurotoxin-mediated cleavage of cellubrevin impairs epithelial cell migration and integrin-dependent cell adhesion". Proc. Natl. Acad. Sci. U.S.A. 102 (18): 6362–7. doi:10.1073/pnas.0409613102. PMC 1088364. PMID 15851685. 
  16. ^ Skalski M, Coppolino MG (October 2005). "SNARE-mediated trafficking of alpha5beta1 integrin is required for spreading in CHO cells". Biochem. Biophys. Res. Commun. 335 (4): 1199–210. doi:10.1016/j.bbrc.2005.07.195. PMID 16112083. 
  17. ^ Tayeb MA, Skalski M, Cha MC, Kean MJ, Scaife M, Coppolino MG (April 2005). "Inhibition of SNARE-mediated membrane traffic impairs cell migration". Exp. Cell Res. 305 (1): 63–73. doi:10.1016/j.yexcr.2004.12.004. PMID 15777788. 
  18. ^ Luftman K, Hasan N, Day P, Hardee D, Hu C (February 2009). "Silencing of VAMP3 inhibits cell migration and integrin-mediated adhesion". Biochem. Biophys. Res. Commun. 380 (1): 65–70. doi:10.1016/j.bbrc.2009.01.036. PMC 2716655. PMID 19159614.