Department of Medicine, Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, CA, USA.
Cell Cycle. 2011 Apr 15;10(8):1225-32. doi: 10.4161/cc.10.8.15343.
Phosphotyrosine signaling in anchored epithelial cells constitutes a spacially ordained signaling program that largely functions to promote integrin-linked focal adhesion complexes, serving to secure cell anchorage to matrix and as a bidirectional signaling hub that coordinates the physical state of the cell and its environment with cellular functions including proliferation and survival. Cells release their adhesions during processes such as mitosis, migration, or tumorigenesis, but the fate of signaling through tyrosine phosphorylation in unanchored cells remains poorly understood. In an examination of epithelial cells in the unanchored state, we find abundant phosphotyrosine signaling, largely recommitted to an anti-adhesive function mediated through the Src family phosphorylation of their transmembrane substrate Trask/CDCP1/gp140. Src-Trask phosphorylation inhibits integrin clustering and focal adhesion assembly and signaling, defining an active phosphotyrosine signaling program underlying the unanchored state. Src-Trask signaling and Src-focal adhesion signaling inactivate each other, constituting two opposing modes of phosphotyrosine signaling that define a switch underline cell anchorage state. Src kinases are prominent drivers of both signaling modes, identifying their position at the helm of adhesion signaling capable of specifying anchorage state through substrate selection. These experimental studies along with concurring phylogenetic evidence suggest that phosphorylation on tyrosine is a signaling function fundamentally linked with the regulation of integrins.
锚定上皮细胞中的磷酸酪氨酸信号构成了一个空间有序的信号程序，主要功能是促进整合素连接的焦点粘附复合物，以确保细胞与基质的附着，并作为一个双向信号枢纽，协调细胞的物理状态及其环境与包括增殖和存活在内的细胞功能。细胞在有丝分裂、迁移或肿瘤发生等过程中释放其附着，但未附着细胞中通过酪氨酸磷酸化的信号命运仍然知之甚少。在对未锚定上皮细胞的检查中，我们发现大量的磷酸酪氨酸信号，主要重新致力于通过Src 家族对其跨膜底物 Trask/CDCP1/gp140 的磷酸化介导的抗粘附功能。Src-Trask 磷酸化抑制整合素聚集和焦点粘附组装和信号传递，定义了未附着状态下的活跃磷酸酪氨酸信号程序。Src-Trask 信号和 Src-焦点粘附信号相互失活，构成了两种相反的磷酸酪氨酸信号模式，定义了细胞附着状态的开关。Src 激酶是这两种信号模式的主要驱动因素，通过选择底物来确定其在粘附信号中的主导地位，从而能够指定附着状态。这些实验研究以及一致的系统发育证据表明，酪氨酸的磷酸化是一种与整合素调节密切相关的信号功能。
