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Tetraspanins (TSPAN) are cell surface proteins and the family contains 34 members in eucaryota (TSPAN1-34) (1,2). Tetraspanins are relatively small proteins in the range of 22-30 kDa and are present in nearly all mammalian cells and many species such as Schistosoma, C. elegans and Drosophila(2).
Each protein consists of four conserved transmembrane domains: characteristic large extracellular loop and short cytoplasmic domains. Extracellular loop contains CCG motif (Cys-Cys-Gly) and most of tetraspanins contain two or four additional Cys residues (2-4).
Tetraspanins do not have any activity nor function as classical cell membrane receptors. However, they serve as an anchor to organize interaction and attachment of other tetraspanins, molecules, proteins, receptors, etc. as well as organization of various membrane complexes. It was reported that they play a role in tissue differentiation; egg-sperm fusion; tumor-cell metastasis; cell proliferation, adhesion and migration; interactions with integrins, matrix metalloproteinases (MMP), growth factor receptors and immunoglobulins (4-9).
Growth factors play an important role in pathogenesis development of pulmonary hypertension (10-12) and tetraspanins were reported to regulate the irreceptors and signalling in cancer cells. Transforming growth factor beta (TGF-β) signalling(13) was affected when tetraspanin CD151 was depleted. Cell migration, proliferation and metastasis were significantly reduced as well as scattering was induced (13). Moreover, TGF-β1- and growth factor-mediated signalling activities modulate tetraspanin TM4SF5 expression which leads to acquisition of mesenchymal cell features, suggesting that TM4SF5 induction may be involved in the development of liver pathologies (14). Additionally, some reports show that tetraspanin CD63 serves as a bridge between β1 integrin and VEGF-R2(15). Moreover, a study by Choi et al. suggests that tetraspaninTM4SF5 and IGF1-R are able to modulate one another and each protein promoting the expression of the other(16).
Tetraspanins have been shown to interact with different members of integrins. These interactions regulate cell adhesion, migration, signalling and crosstalk with extracellular matrix and adherent junctions which as a result induce tumor invasion, metastasis and progression(4-7).
Tetraspanin family is well recognized and investigated in cancer.However, despite importance and function of tetraspanins in many diseases, there are no reports so far regarding them in pulmonary hypertension. As described above targeting tetraspanins offers attractive novel therapeutics to attenuate cancer changes.
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11. Kosanovic D et al., Transforming growth factor-β signaling in schistosomiasis-induced pulmonary hypertension: a perspective for antifibrotic drugs?Circulation. 2013 Sep 17;128(12)
12. Ogo T et al., Inhibition of overactive transforming growth factor-β signaling by prostacyclin analogs in pulmonary arterial hypertension.Am J Respir Cell Mol Biol. 2013 Jun;48(6)
13. Sadej R., et al. Tetraspanin CD151 regulates transforming growth factor beta signaling: implication in tumor metastasis.Cancer Res. 2010 Jul 15;70(14)
14. Kang M et al., Cross-talk between TGFβ1 and EGFR signalling pathways induces TM4SF5 expression and epithelial-mesenchymal transition. Biochem J. 2012 May 1;443(3)
15. Tugues S., et al. Tetraspanin CD63 promotes vascular endothelial growth factor receptor 2-β1 integrin complex formation, thereby regulating activation and downstream signaling in endothelial cells in vitro and in vivo.J Biol Chem. 2013 Jun 28;288(26).
16. Choi J., et al. Bidirectional signaling between TM4SF5 and IGF1R promotes resistance to EGFR kinase inhibitors.Lung Cancer. 2015 Oct;90(1)