title: Tetraspanin CD151 regulates transforming growth factor beta signaling: implication in tumor metastasis.
abstract: Tetraspanin CD151 is associated with laminin-binding integrins and controls tumor cell migration and invasion. By analyzing responses of breast cancer cells to various growth factors, we showed that depletion of CD151 specifically attenuates transforming growth factor beta1 (TGFbeta1)-induced scattering and proliferation of breast cancer cells in three-dimensional Matrigel. CD151-dependent cell scattering requires its association with either alpha3beta1 or alpha6 integrins, but it is independent of the recruitment of CD151 to tetraspanin-enriched microdomains. We also found that CD151 regulates the compartmentalization of TGF-beta type I receptor (TbetaRI/ALK-5) and specifically controls the TGFbeta1-induced activation of p38. In contrast, signaling leading to activation of Smad2/3, c-Akt, and Erk1/2 proteins was comparable in CD151(+) and CD151(-) cells. Attenuation of TGFbeta1-induced responses correlated with reduced retention in the lung vascular bed, inhibition of pneumocyte-induced scattering of breast cancer cells in three-dimensional Matrigel, and decrease in experimental metastasis to the lungs. These results identify CD151 as a positive regulator of TGFbeta1-initiated signaling and highlight the important role played by this tetraspanin in TGFbeta1-induced breast cancer metastasis.
authors.affiliation: Department of Pathology, School of Cancer Sciences, The University of Birmingham, Edgbaston, Birmingham, United Kingdom.
authors.forename: Rafal
authors.initials: R
authors.lastname: Sadej
authors.forename: Hanna
authors.initials: H
authors.lastname: Romanska
authors.forename: Dean
authors.initials: D
authors.lastname: Kavanagh
authors.forename: Gouri
authors.initials: G
authors.lastname: Baldwin
authors.forename: Takashi
authors.initials: T
authors.lastname: Takahashi
authors.forename: Neena
authors.initials: N
authors.lastname: Kalia
authors.forename: Fedor
authors.initials: F
authors.lastname: Berditchevski
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D003094:Collagen; D004338:Drug Combinations; D004847:Epithelial Cells / Q000473:pathology; D005260:Female; D006801:Humans; D016023:Integrins / Q000378:metabolism; D007797:Laminin; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology / Q000556:secondary*; D008297:Male; D021962:Membrane Microdomains; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D011509:Proteoglycans; D015398:Signal Transduction; D060185:Tetraspanin 24; D053773:Transforming Growth Factor beta1 / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D015703:Antigens, CD; C554715:CD151 protein, human; C554716:Cd151 protein, mouse; D004338:Drug Combinations; D016023:Integrins; D007797:Laminin; D011509:Proteoglycans; D060185:Tetraspanin 24; D053773:Transforming Growth Factor beta1; C059485:matrigel; D003094:Collagen