Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6160, USA.
Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6160, USA.
Cell Signal. 2012 Feb;24(2):353-362. doi: 10.1016/j.cellsig.2011.08.011. Epub 2011 Aug 27.
Rac GTPases, small G-proteins widely implicated in tumorigenesis and metastasis, transduce signals from tyrosine-kinase, G-protein-coupled receptors (GPCRs), and integrins, and control a number of essential cellular functions including motility, adhesion, and proliferation. Deregulation of Rac signaling in cancer is generally a consequence of enhanced upstream inputs from tyrosine-kinase receptors, PI3K or Guanine nucleotide Exchange Factors (GEFs), or reduced Rac inactivation by GTPase Activating Proteins (GAPs). In breast cancer cells Rac1 is a downstream effector of ErbB receptors and mediates migratory responses by ErbB1/EGFR ligands such as EGF or TGFα and ErbB3 ligands such as heregulins. Recent advances in the field led to the identification of the Rac-GEF P-Rex1 as an essential mediator of Rac1 responses in breast cancer cells. P-Rex1 is activated by the PI3K product PIP3 and Gβγ subunits, and integrates signals from ErbB receptors and GPCRs. Most notably, P-Rex1 is highly overexpressed in human luminal breast tumors, particularly those expressing ErbB2 and estrogen receptor (ER). The P-Rex1/Rac signaling pathway may represent an attractive target for breast cancer therapy.
Rac GTPases 是一种广泛参与肿瘤发生和转移的小 G 蛋白，可将酪氨酸激酶、G 蛋白偶联受体 (GPCR) 和整合素的信号转导，并控制包括运动性、黏附性和增殖性在内的许多重要细胞功能。Rac 信号的失调通常是由于来自酪氨酸激酶受体、PI3K 或鸟苷酸交换因子 (GEF) 的增强上游输入，或由于 GTP 酶激活蛋白 (GAP) 对 Rac 的失活减少而导致的。在乳腺癌细胞中，Rac1 是 ErbB 受体的下游效应物，并通过 ErbB1/EGFR 配体（如 EGF 或 TGFα）和 ErbB3 配体（如 heregulin）介导迁移反应。该领域的最新进展导致鉴定出 Rac-GEF P-Rex1 是乳腺癌细胞中 Rac1 反应的重要介质。P-Rex1 被 PI3K 产物 PIP3 和 Gβγ 亚基激活，并整合来自 ErbB 受体和 GPCR 的信号。值得注意的是，P-Rex1 在人腔乳腺癌肿瘤中高度过表达，特别是那些表达 ErbB2 和雌激素受体 (ER) 的肿瘤。P-Rex1/Rac 信号通路可能是乳腺癌治疗的一个有吸引力的靶点。
