BST1/CD157
Proteins

DEFINITION

BST1 gene is located on chromosomes 4p15 and encodes for a GPI anchored protein of 42-45 kDa. It is an ADP-ribosyl cyclase–related cell surface molecule and regulates leukocyte diapedesis during inflammation. BST1 is also involved in epithelial-mesenchimal transition of ovarian cancer and might be a good candidate as a therapeutic target for tumors characterized by high BST1 expression.

Database	Link
Wikigenes	BST1
GeneCard	BST1
OMIM	BST1
iHOP	BST1

CHEMICAL STRUCTURE AND IMAGES

• Primary structure: the primary sequence present a core of 31kDa with four glicosilation site in the residues 66, 95, 148, 192 of Asparagin. This modification are essential for corretc folding and function of protein (Site-directed removal of N-glycosylation sites in BST-1/CD157: effects on molecular and functional heterogeneity, 2001). The Cystein residues 119, 160, 173 and 201 are important for the synthesis and hydrolysis of cADPR (Identification of the enzymatic active site of CD38 by site-directed mutagenesis, 2000). Moreover there are a region rich of leucin involved in homotypic and heterotypic interaction.
• Secondary structure: the alpha-helix is the predominant structure, as shown in the underlyng picture.

• Tertiary structure
• Quaternary structure: BST1 is present as omodimer or eterodimer.

Protein Aminoacids Percentage

ENZYMATIC ACTIVITY

BST1 is an enzyme similar in function and structure to CD38. BST1 has a duplex activity: ADP-ribosyl ciclase and cADPR-hydrolase, the second prevails on the first. BST1 produces cADPR from NAD+, then it hydrolyzes cADPR obtaining ADPR. Its activity needs of particular conditions: a pH value between 4 and 6 and the presence of bivalent ions, such as Zn²⁺ and Mn²⁺. The ions Cu²⁺ inhibit BST1 activity. These facts suggest that the activity of BST1 is not rilevant in physiological condition. Its biological function is probably mediated by its interaction with integrins, in particular CD29 and CD18 (The CD157-integrin partnership controls transendothelial migration and adhesion of human monocytes, 2011).

CELLULAR FUNCTIONS

Both CD38 and BST1 play dual roles as receptors and ectoenzymes. Its engagement regulates Ca²⁺ homeostasis and mediates superoxide (O₂) production. BST1 plays a pivotal role in the control of leukocyte adhesion, migration and diapedesis.

Neutrophilis model
The importance of BST1 in the neutrophil diapedesis was demostrated using monoclonal antibodies: ligation of BST1 with monoclonal antibodies on the surface of neutrophilis results in altered neutrophil movement on the surface of endothelium and in loss of diapedesis. Studies revealed that this protein has a sort of compass during the interaction between endothelial cells and neutrophilis. The crosslinking of BST1 induce morfology modification in the cytoplasmic membrane of neutrophilis, including the formation of microprotrusion and lamellipodia. At the same time, BST1, that is fisiologically distributed all over the membrane, is concentrated in the uropod, in the opposite site of lamellipodia, that are regions rich of polimerized actin (CD157 is an important mediator of neutrophil adhesion and migration, 2004).

Following BST1 ligation, neutrophils appear disoriented, meandering toward junctions where they eventually stop without transmigrating (CD157 plays a pivotal role in neutrophil transendothelial migration 2006).

Monocytes model
BST1 is prevalently located within the detergent-resistant membrane microdomains (lipid raft) to which, upon clustering, it promotes the recruitment of CD18 and CD29 integrin, which, in turn, leads to the formation of a multimolecular complex favoring signal transduction. This functional cross-talk with integrins allows BST1 to act as a receptor despite its intrinsic structural inability to do so on its own. Intracellular signals mediated by BST1 rely on the integrin/Src/FAK (focal adhesion kinase) pathway, resulting in increased activity of the MAPK/ERK1/2 and the PI3K/Akt downstream signaling pathways, which are crucial in the control of monocyte transendothelial migration. Collectively, these findings indicate that BST1 acts as a molecular organizer of signaling-competent membrane microdomains and that it forms part of a larger molecular machine ruled by integrins. The CD157-integrin partnership provides optimal adhesion and transmigration of human monocytes (The CD157-integrin partnership controls transendothelial migration and adhesion of human monocytes, 2011).

Ovarian cancer model
The involvement of BST1 in the control of leukocyte trafficking and its expression outside the myeloid compartment primarily in mesothelial cells, led to hypothesize that BST1 could be expressed by epithelial ovarian cancer cells and could be involved in the control of tumor dissemination. BST1 is involved in EMT of ovarian cancer cells. Indeed, exogenous expression of BST1 promotes morphological, phenotypic and functional changes that are considered the hallmarks of mesenchymal differentiation. The expression of BST1 led to the expression of molecules that are reported to identify a subset of cells with a stem-like phenotype, such as EpCAM, CD24 and SSEA4 (Stage-specific embryonic antigen 4). The connection between EMT and cancer stem cell generation has a detrimental effect on cancer progression because it entails the acquisition of cellular traits associated with high-grade malignancy and with self-renewal ability, both of which foster metastatic dissemination. BST1-positive cells show accelerated growth and a higher proliferation rate than the negative counterpart, resulting in a significantly greater tumorigenic potential in vivo (Biological Role, Clinical Significance and Potential Therapeutic Applications of CD157 in Ovarian Cancer, 2013, in press).

Tissue distribution (CD38 and CD157: A long journey from activation markers to multifunctional molecules, 2013)

BST1 AND DISEASES

• BST1 is involved in dissemination of ovarian cancer cell. It was expressed by ovarian cancer cells and it potentiated the adhesion, migration, and invasion of serous ovarian cancer cells through different extracellular matrices. BST1-transfected ovarian cancer cells migrated twice as much as BST1-negative control cells. Blockage of BST1 inhibited mesothelial invasion by serous ovarian cancer cells in a three-dimensional model. (Functional Role and Prognostic Significance of CD157 in Ovarian Carcinoma, 2010).
  BST1 may be helpful in clinical practice. Indeed, used in conjunction with conventional diagnostic markers, it could help formulate dependable prognostic criteria and address the classification of ovarian cancers into molecular subtypes with different outcomes. Finally, the ability of BST1 blocking mAb to prevent EOC invasion and dissemination in vitro suggests that BST1 could be a promising therapeutic target for intraperitoneal antibody-based therapy as an additional modality complementing surgery and chemotherapy (Biological Role, Clinical Significance and Potential Therapeutic Applications of CD157 in Ovarian Cancer, 2013, in press).
• BST1 gene's polymorphism has been associated with Parkinson's disease, it was confirmed by several study of gnome wide-association studies (Genome-wide association study confirms BST1 and suggests a locus on 12q24 as the risk loci for Parkinson's disease in the European populatio, 2011). Nevertheless recent studies have been underlied that the relationship between BST1 SNPs rs11931532, rs12645693, and rs11724635 sporadic PD was not significative however the relationship between SNP rs11724635 and sporadic PD was of borderline significance (Lack of association between BST1 polymorphisms and sporadic Parkinson's disease in a Japanese population, 2012).
• BST1-deficient neutrophils obtained from patients with paroxysmal nocturnal hemoglobinuria (PNH) are characterized by a severely impaired diapedesis (CD157 plays a pivotal role in neutrophil transendothelial migration, 2006).

Authors
Augeri Stefania
Mariani Valentina