Wendt Michael K, Smith Jason A, Schiemann William P
Department of Pharmacology, University of Colorado, Denver, Anschutz Medical Campus, Aurora, Colorado 80045, USA.
J Biol Chem. 2009 Dec 4;284(49):34145-56. doi: 10.1074/jbc.M109.023614. Epub 2009 Oct 12.
During breast cancer progression, transforming growth factor-beta (TGF-beta) switches from a tumor suppressor to a pro-metastatic molecule. Several recent studies suggest that this conversion in TGF-beta function depends upon fundamental changes in the TGF-beta signaling system. We show here that these changes in TGF-beta signaling are concomitant with aberrant expression of the focal adhesion protein, p130Cas. Indeed, elevating expression of either the full-length (FL) or just the carboxyl terminus (CT) of p130Cas in mammary epithelial cells (MECs) diminished the ability of TGF-beta1 to activate Smad2/3, but increased its coupling to p38 MAPK. This shift in TGF-beta signaling evoked (i) resistance to TGF-beta-induced growth arrest, and (ii) acinar filling upon three-dimensional organotypic cultures of p130Cas-FL or -CT expressing MECs. Furthermore, rendering metastatic MECs deficient in p130Cas enhanced TGF-beta-stimulated Smad2/3 activity, which restored TGF-beta-induced growth inhibition both in vitro and in mammary tumors produced in mice. Additionally, whereas elevating TbetaR-II expression in metastatic MECs had no affect on their phosphorylation of Smad2/3, this event markedly enhanced their activation of p38 MAPK, leading to increased MEC invasion and metastasis. Importantly, depleting p130Cas expression in TbetaR-II-expressing metastatic MECs significantly increased their activation of Smad2/3, which (i) reestablished the physiologic balance between canonical and noncanonical TGF-beta signaling, and (ii) reversed cellular invasion and early mammary tumor cell dissemination stimulated by TGF-beta. Collectively, our findings identify p130Cas as a molecular rheostat that regulates the delicate balance between canonical and noncanonical TGF-beta signaling, a balance that is critical to maintaining the tumor suppressor function of TGF-beta during breast cancer progression.
在乳腺癌进展过程中，转化生长因子-β（TGF-β）从肿瘤抑制因子转变为促转移分子。最近的几项研究表明，TGF-β功能的这种转变取决于TGF-β信号系统的根本变化。我们在此表明，TGF-β信号的这些变化与粘着斑蛋白p130Cas的异常表达同时发生。事实上，在乳腺上皮细胞（MECs）中提高全长（FL）或仅p130Cas的羧基末端（CT）的表达，会降低TGF-β1激活Smad2/3的能力，但会增加其与p38丝裂原活化蛋白激酶（MAPK）的偶联。TGF-β信号的这种转变引发了（i）对TGF-β诱导的生长停滞的抗性，以及（ii）表达p130Cas-FL或-CT的MECs在三维器官型培养中的腺泡填充。此外，使转移性MECs中的p130Cas缺失增强了TGF-β刺激的Smad2/3活性，这在体外和小鼠产生的乳腺肿瘤中都恢复了TGF-β诱导的生长抑制。此外，虽然在转移性MECs中提高TβR-II的表达对其Smad2/3的磷酸化没有影响，但这一事件显著增强了它们对p38 MAPK的激活，导致MECs侵袭和转移增加。重要的是，在表达TβR-II的转移性MECs中耗尽p130Cas的表达显著增加了它们对Smad2/3的激活，这（i）重新建立了经典和非经典TGF-β信号之间的生理平衡，以及（ii）逆转了TGF-β刺激的细胞侵袭和早期乳腺肿瘤细胞扩散。总的来说，我们的研究结果确定p130Cas是一种分子变阻器，可调节经典和非经典TGF-β信号之间的微妙平衡，这种平衡对于在乳腺癌进展过程中维持TGF-β的肿瘤抑制功能至关重要。
