[HTML][HTML] Genesis and reversal of the ischemic phenotype in epithelial cells

KT Bush, SH Keller, SK Nigam - The Journal of clinical …, 2000 - Am Soc Clin Investig
KT Bush, SH Keller, SK Nigam
The Journal of clinical investigation, 2000Am Soc Clin Investig
In cell culture models, polarization and intercellular junctions depend in large part on cell-
cell contact mediated by E-cadherin and subsequent assembly of the AJ. For example,
treatment of polarizing epithelial cells with anti–E-cadherin antibodies disrupts junction
assembly and retards the generation of the polarized epithelial phenotype (14).
Alternatively, transfection of E-cadherin into nonpolarized fibroblasts induces a polarized
distribution of NaKATPase somewhat akin to that seen in polarized epithelial cells (15). In …
In cell culture models, polarization and intercellular junctions depend in large part on cell-cell contact mediated by E-cadherin and subsequent assembly of the AJ. For example, treatment of polarizing epithelial cells with anti–E-cadherin antibodies disrupts junction assembly and retards the generation of the polarized epithelial phenotype (14). Alternatively, transfection of E-cadherin into nonpolarized fibroblasts induces a polarized distribution of NaKATPase somewhat akin to that seen in polarized epithelial cells (15). In addition, the cadherin-catenin interactions within the AJ are also critical to the formation and maintenance of the polarized epithelia (16). ATP depletion of cultured renal epithelial cells results in rapid internalization of E-cadherin (17). Even under normal physiological conditions, E-cadherin is selectively internalized and recycled to the cell surface in a clathrin-mediated recycling endosomal pathway (18); it remains to be determined whether this or another pathway is involved in internalization and re-sorting of E-cadherin after ischemia. A somewhat more prolonged insult leads not only to internalization of E-cadherin, but also to proteolytic clipping of this protein at a specific site and to the disruption of normal cadherin-catenin interactions (8). Identification of the site of E-cadherin cleavage as well as the protease involved will shed considerable mechanistic light on the disruption of the AJ in ischemia. Interestingly, although E-cadherin itself is cleaved, its cytoplasmic binding partners the catenins remain near their steady-state levels for prolonged periods of ATP depletion (8). Because functional AJs are critical for the establishment and maintenance of tight polarized epithelia (including TJ formation and polarized sorting of membrane proteins), degradation of E-cadherin, as well as disruption of cadherin-catenin interactions, likely constitutes a critical lesion in epithelial ischemia. Over the long term, reassembly of the AJ in recovering epithelial tissue must depend on resynthesis of E-cadherin, assembly with the catenins, and re-formation of functional AJs. How this occurs remains unclear, although it is possible that the undegraded catenins are recruited from the cytoplasm and reassembled with de novo synthesized E-cadherin at the endoplasmic reticulum (ER) itself or at a more distal compartment in the secretory pathway, after which they may be targeted to the cell surface to help reconstruct the AJ. Repair of more permanent AJ structures might depend on turnover of the proteins exposed to ischemic injury and on the de novo synthesis and assembly of new components. As discussed later here, a limiting factor in the face of sustained ischemia may be the inability of the ER to fold newly synthesized membrane and secreted proteins such as E-cadherin (4).
The Journal of Clinical Investigation