Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2024 Jan 19;13(2):193.
doi: 10.3390/cells13020193.

Molecular Regulation and Oncogenic Functions of TSPAN8

Jicheng Yang  1   2   3 , Ziyan Zhang  2   3 , Joanne Shi Woon Lam  4 , Hao Fan  4 , Nai Yang Fu  1   2   3   5
Affiliations
Review

Molecular Regulation and Oncogenic Functions of TSPAN8

Jicheng Yang et al. Cells. .

Abstract

Tetraspanins, a superfamily of small integral membrane proteins, are characterized by four transmembrane domains and conserved protein motifs that are configured into a unique molecular topology and structure in the plasma membrane. They act as key organizers of the plasma membrane, orchestrating the formation of specialized microdomains called "tetraspanin-enriched microdomains (TEMs)" or "tetraspanin nanodomains" that are essential for mediating diverse biological processes. TSPAN8 is one of the earliest identified tetraspanin members. It is known to interact with a wide range of molecular partners in different cellular contexts and regulate diverse molecular and cellular events at the plasma membrane, including cell adhesion, migration, invasion, signal transduction, and exosome biogenesis. The functions of cell-surface TSPAN8 are governed by ER targeting, modifications at the Golgi apparatus and dynamic trafficking. Intriguingly, limited evidence shows that TSPAN8 can translocate to the nucleus to act as a transcriptional regulator. The transcription of TSPAN8 is tightly regulated and restricted to defined cell lineages, where it can serve as a molecular marker of stem/progenitor cells in certain normal tissues as well as tumors. Importantly, the oncogenic roles of TSPAN8 in tumor development and cancer metastasis have gained prominence in recent decades. Here, we comprehensively review the current knowledge on the molecular characteristics and regulatory mechanisms defining TSPAN8 functions, and discuss the potential and significance of TSPAN8 as a biomarker and therapeutic target across various epithelial cancers.

Keywords: TSPAN8; cancer metastasis; cancer stem cell; cell invasion; cell signaling; exosome; plasma membrane; stem cell; tetraspanin; tetraspanin-enriched microdomain; tumor-associated antigen.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Topology and structure of TSPAN8 in the membrane. (A) Schematic diagram for the topology of human TSPAN8 in the plasma membrane. TSPAN8 contains four transmembrane domains (TM1-4), one inner loop and two extracellular loops (SEL: small extracellular loop and LEL: large extracellular loop). The six cysteine residues, with two in the conserved CCG motif of the tetraspanin superfamily, form three disulfide bonds as indicated. N118 in LEL is the conserved and sole N-glycosylation site of TSPAN8. Created with BioRender.com, accessed on 16 January 2024. (B) Overlap of TSPAN8 structures generated by AlphaFold (green) modeling and the TSPAN8 homology modeling (HM6K4J, white) based on CD9 template (PDB ID: 6K4J), with three disulfide bonds in the LEL domain for both. In HM6K4J, the LEL domain is more loosely packed and located nearer to the extracellular membrane plane than that of the AlphaFold model. The AlphaFold model forms a tightly packed LEL architecture, with a longer alpha helix formed between residues Glu133 to Phe149 (circled as a in figure) compared to the same region in HM6K4J, which is located closer to the extracellular membrane plane, and it has a shorter alpha helix formed between residues Glu133 to Ala141 instead (circled as b in figure). One β-sheet is formed within the region from residues Cys181 to Tyr190 in the AlphaFold model (circled as c) but not in HM6K4J. Furthermore, compared to HM6K4J, the TM2, TM3 and TM1 are further away from each other in the AlphaFold model. (C) Docking conformation of cholesterol in the TSPAN8 homology model HM6K4J. In contrast to crystal structure of CD81 (PDB ID: 5TCX), the β-hydroxyl group of the docked cholesterol in HM6K4J interacts with Asn16 (N16) sidechain (orange) through H-bonding, probably because Glu219 in CD81 is not conserved in TSPAN8 but replaced by Gly223. This may lead to the β-face of cholesterol turning towards TM1 and TM2 instead. The rigid sterol ring of cholesterol is also further stabilized by hydrophobic sidechains (cyan sticks) of residues at the binding site: Phe15/Phe19/Phe88, Leu69/Leu92/Leu216 and Ile65/Ile66/Ile95/Ile219.
Figure 2
Figure 2
TSPAN8 recruits different protein partners into TEMs for diverse molecular and signaling processes. (A) Interaction of TSPAN8 with different tetraspanin members. (B) Interaction of TSPAN8 with adhesion proteins, including β1 integrins, EpCAM, E-cadherin, p120-catenin, and β-catenin. These interactions are involved in regulating cell adhesion, migration, and cell signaling, potentially contributing to tumor progression and metastasis. (C) Interaction of TSPAN8 with distinct membrane metalloproteases, such as ADAMs, MMPs, ECE1 and ACE2. (D) Interaction of TSPAN8 with different cell-surface receptors, participating in receptor-mediated signaling pathways. These receptors include LGR5, RTKs (receptor tyrosine kinases), GPCRs (G-protein coupled receptors), EGFR, PTCH1 (protein patched homolog 1) and CD44. Of note is that all the interactions shown here are based on published papers. Some interactions may be indirect. Created with BioRender.com, accessed on 19 January 2024.
Figure 3
Figure 3
Molecular regulation of TSPAN8′s oncogenic functions. The oncogenic functions of TSPAN8 are controlled by multiple mechanisms, including transcriptional activation and repression, ER targeting, Golgi modification, cell-surface presentation, exosome biogenesis and nuclear translocation. TSPAN8 transcription is governed within the nucleus by a network of activators (dark green) and repressors (light blue). TSPAN8 protein is targeted through the ER by TMEM208, undergoing post-translation modifications at the Golgi apparatus before it moves to the cell surface. The presentation of TSPAN8 in the cell surface is regulated by a couple of proteins in the Golgi, including MGAT1/2, SPPL3 and B3GNT5. TSPAN8 can translocate back to the nucleus and serve as a transcriptional cofactor for the transcription factors, such as STAT3 and AR, to promote the expression of oncogenic genes. TSPAN8 also plays a pivotal role in exosome biogenesis, a process that is initiated by the formation of early endosomes (EEs) through vesicle uptake and recycling which subsequently progress into multivesicular bodies (MVBs), where cargo is incorporated into intraluminal vesicles (ILVs). Exosomes are ultimately formed and released from the cell. Created with BioRender.com, accessed on 16 January 2024.
Figure 4
Figure 4
TSPAN8 as a biomarker and therapeutic target of cancer. The schematic representation of strategies targeting TSPAN8 at different stages of tumor progression. TSAPN8 expression has been shown to be a molecular marker for cancer stem cells (CSCs) or cancer-initiating cells (CICs). Multiple monoclonal anti-TSPAN8 monoclonal antibodies have been shown to impair cancer progression. They may restrain primary tumor growth and block the migration/invasion of cancer cells, which in turn prevents metastasis. Anti-TSPAN8 antibodies may also suppress the formation of tumor-promoting microenvironments by inhibiting the biogenesis and release of cancer cell-derived exosomes. Additionally, CAR-T cells targeting TSPAN8 may be a novel promising strategy for treatment of various epithelial cancers with TSPAN8 expression. Moreover, detection of TSPAN8-expressing circulating tumor cells or exosomes potentially represents a non-invasive approach for diagnosis and prognosis of various epithelial cancers. Created with BioRender.com, accessed on 16 January 2024.
See this image and copyright information in PMC

Similar articles

See all similar articles

References

    1. Charrin S., Jouannet S., Boucheix C., Rubinstein E. Tetraspanins at a glance. J. Cell Sci. 2014;127:3641–3648. doi: 10.1242/jcs.154906. - DOI - PubMed
    1. Bonnet M., Maisonial-Besset A., Zhu Y., Witkowski T., Roche G., Boucheix C., Greco C., Degoul F. Targeting the Tetraspanins with Monoclonal Antibodies in Oncology: Focus on Tspan8/Co-029. Cancers. 2019;11:179. doi: 10.3390/cancers11020179. - DOI - PMC - PubMed
    1. Titu S., Grapa C.M., Mocan T., Balacescu O., Irimie A. Tetraspanins: Physiology, Colorectal Cancer Development, and Nanomediated Applications. Cancers. 2021;13:5662. doi: 10.3390/cancers13225662. - DOI - PMC - PubMed
    1. Hemler M.E. Tetraspanin functions and associated microdomains. Nat. Rev. Mol. Cell Biol. 2005;6:801–811. doi: 10.1038/nrm1736. - DOI - PubMed
    1. Zemni R., Bienvenu T., Vinet M.C., Sefiani A., Carrie A., Billuart P., McDonell N., Couvert P., Francis F., Chafey P., et al. A new gene involved in X-linked mental retardation identified by analysis of an X;2 balanced translocation. Nat. Genet. 2000;24:167–170. doi: 10.1038/72829. - DOI - PubMed

Publication types

LinkOut - more resources