Blood vessel epicardial substance

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).{{cite journal | vauthors = Andrée B, Hillemann T, Kessler-Icekson G, Schmitt-John T, Jockusch H, Arnold HH, Brand T | title = Isolation and characterization of the novel popeye gene family expressed in skeletal muscle and heart | journal = Developmental Biology | volume = 223 | issue = 2 | pages = 371–82 | date = Jul 2000 | pmid = 10882522 | doi = 10.1006/dbio.2000.9751 | doi-access = free }}{{cite journal | vauthors = Reese DE, Zavaljevski M, Streiff NL, Bader D | title = bves: A novel gene expressed during coronary blood vessel development | journal = Developmental Biology | volume = 209 | issue = 1 | pages = 159–71 | date = May 1999 | pmid = 10208750 | doi = 10.1006/dbio.1999.9246 | doi-access = free }} Although initially isolated from cardiac tissue, it was later revealed that Bves is highly expressed in muscle, epithelial and brain tissue. Most studies have focused on determining the function of Bves in epithelial tissue at the cellular level.

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.

Bves is a three-pass transmembrane protein with a short extracellular N-terminus (~40aa) and a larger intracellular C-terminus (~250aa).{{cite journal | vauthors = Knight RF, Bader DM, Backstrom JR | title = Membrane topology of Bves/Pop1A, a cell adhesion molecule that displays dynamic changes in cellular distribution during development | journal = The Journal of Biological Chemistry | volume = 278 | issue = 35 | pages = 32872–9 | date = Aug 2003 | pmid = 12815060 | doi = 10.1074/jbc.M301961200 | doi-access = free }} 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.{{cite journal | vauthors = Kawaguchi M, Hager HA, Wada A, Koyama T, Chang MS, Bader DM | title = Identification of a novel intracellular interaction domain essential for Bves function | journal = PLOS ONE | volume = 3 | issue = 5 | pages = e2261 | year = 2008 | pmid = 18493308 | pmc = 2373926 | doi = 10.1371/journal.pone.0002261 | bibcode = 2008PLoSO...3.2261K | doi-access = free }} {{open access}}

Bves is expressed in muscle, epithelial and brain tissue, and is thus found in many adult organs. During development, Bves is detected in all three germ layers and later localizes to the aforementioned tissues.{{cite journal | vauthors = Osler ME, Bader DM | title = Bves expression during avian embryogenesis | journal = Developmental Dynamics | volume = 229 | issue = 3 | pages = 658–67 | date = Mar 2004 | pmid = 14991721 | doi = 10.1002/dvdy.10490 | s2cid = 12458928 | doi-access = free }} 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.

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. Bves also interacts with VAMP3, a SNARE protein important for vesicle fusion. 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.

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 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.

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.{{cite journal | vauthors = McMahon HT, Ushkaryov YA, Edelmann L, Link E, Binz T, Niemann H, Jahn R, Südhof TC | title = Cellubrevin is a ubiquitous tetanus-toxin substrate homologous to a putative synaptic vesicle fusion protein | journal = Nature | volume = 364 | issue = 6435 | pages = 346–9 | date = Jul 1993 | pmid = 8332193 | doi = 10.1038/364346a0 | bibcode = 1993Natur.364..346M | s2cid = 4324845 }}{{cite journal | vauthors = Proux-Gillardeaux V, Gavard J, Irinopoulou T, Mège RM, Galli T | title = Tetanus neurotoxin-mediated cleavage of cellubrevin impairs epithelial cell migration and integrin-dependent cell adhesion | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 102 | issue = 18 | pages = 6362–7 | date = May 2005 | pmid = 15851685 | pmc = 1088364 | doi = 10.1073/pnas.0409613102 | bibcode = 2005PNAS..102.6362P | url = https://hal.archives-ouvertes.fr/hal-00007763/document | doi-access = free }}{{cite journal | vauthors = Skalski M, Coppolino MG | title = SNARE-mediated trafficking of alpha5beta1 integrin is required for spreading in CHO cells | journal = Biochemical and Biophysical Research Communications | volume = 335 | issue = 4 | pages = 1199–210 | date = Oct 2005 | pmid = 16112083 | doi = 10.1016/j.bbrc.2005.07.195 }}{{cite journal | vauthors = Tayeb MA, Skalski M, Cha MC, Kean MJ, Scaife M, Coppolino MG | title = Inhibition of SNARE-mediated membrane traffic impairs cell migration | journal = Experimental Cell Research | volume = 305 | issue = 1 | pages = 63–73 | date = Apr 2005 | pmid = 15777788 | doi = 10.1016/j.yexcr.2004.12.004 }}{{cite journal | vauthors = Luftman K, Hasan N, Day P, Hardee D, Hu C | title = Silencing of VAMP3 inhibits cell migration and integrin-mediated adhesion | journal = Biochemical and Biophysical Research Communications | volume = 380 | issue = 1 | pages = 65–70 | date = Feb 2009 | pmid = 19159614 | pmc = 2716655 | doi = 10.1016/j.bbrc.2009.01.036 }} 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.

Bves is silenced by promoter hypermethylation in malignancy. 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.

{{Reflist|33em}}

• {{UCSC gene info|BVES}}
• {{UCSC gene info|POP1}}