Figure 7
Schematic representation of LPA-induced NHERF1 regulation and its implication for cancer progression. (a) In the resting state, dormant ERM proteins, which exist as inactive monomers or oligomers, localize primarily to the plasma membrane via interaction with PIP2. (b) Upon LPA stimulation, ERM proteins are rapidly phosphorylated at the C terminus and undergo a phosphorylation-induced transition to active monomers at the plasma membrane. (c) NHERF1 is recruited to membrane-anchored cpERM proteins through the ERM-binding region at the NHERF1 C terminus. (d) The membrane-targeted NHERF1–cpERM complex stabilizes ERM phosphorylation to play a key role as a molecular scaffold, tethering multiple membranous and cytosolic partners just beneath the plasma membrane, which leads to the dynamic reorganization of the cell cortex. (e) Human epithelium is composed of cellular monolayers in which individual cells are tightly linked to their neighbors by tight junctions. In normal epithelium, NHERF1 localizes exclusively in the apical microvilli of the polarized epithelial cells and plays broad roles ranging from regulation of apical proteins to morphogenesis of the apical membrane itself. However, during the epithelial–mesenchymal transition (EMT), innately polar cells lose the cell-to-cell junctions that are required for epithelial integrity and thus lose intrinsic membrane polarity. Eventually, these post-EMT cells behave in an ‘amoeboid’ manner, and are capable of freely moving in any direction. Here we propose a working model in which cytosolic NHERF1 in cancerous amoeboid cells can be dynamically redistributed toward extracellular stimuli via interaction with cpERM, and play a key role in the chemotactic cell migration by resetting the front–rear polarity.
