Department of Pathology, School of Cancer Sciences, The University of Birmingham, Edgbaston, Birmingham, United Kingdom.
Cancer Res. 2010 Jul 15;70(14):6059-70. doi: 10.1158/0008-5472.CAN-09-3497. Epub 2010 Jun 22.
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.
四跨膜蛋白 CD151 与层粘连蛋白结合整合素有关，可控制肿瘤细胞的迁移和侵袭。通过分析乳腺癌细胞对各种生长因子的反应，我们发现，CD151 的耗竭特异性地减弱了转化生长因子 β1（TGFβ1）诱导的乳腺癌细胞在三维 Matrigel 中的散射和增殖。CD151 依赖性细胞散射需要其与 α3β1 或 α6 整合素结合，但不依赖于 CD151 募集到富含四跨膜蛋白的微区。我们还发现，CD151 调节 TGF-β 型 I 受体（TβRI/ALK-5）的分隔，并特异性控制 TGFβ1 诱导的 p38 的激活。相比之下，导致 Smad2/3、c-Akt 和 Erk1/2 蛋白激活的信号在 CD151(+)和 CD151(-)细胞中是相似的。TGFβ1 诱导反应的减弱与在肺血管床中的滞留减少、抑制肺细胞诱导的乳腺癌细胞在三维 Matrigel 中的散射以及实验性转移到肺部的减少有关。这些结果表明 CD151 是 TGFβ1 起始信号的正调节剂，并强调了这种四跨膜蛋白在 TGFβ1 诱导的乳腺癌转移中的重要作用。
