Figure 4.

Molecular mechanisms of leak and pore pathway regulation. (A) Tight junction complex remodeling at steady-state and in response to tumor necrosis factor (TNF). Dashed black lines indicate energy-independent diffusion of claudins (green, blue) and occludin (red) within the membrane; the mobile fractions of occludin and claudin are both increased by TNF. Solid black lines indicate energy-dependent zonula occludens-1 (ZO-1) (orange) exchange between tight junction and cytosolic pools. Occludin endocytosis (white arrow) is driven by TNF-induced myosin light chain kinase (MLCK) activation and requires both caveolin-1 and ZO-1. (B) Phosphorylation regulates interactions between tight junction proteins and can be exploited to modify claudin-2 channel activity. Diagram shows interactions and dynamic behavior of proteins involved in tight junction regulation by casein kinase 2 (CK2). Upper panel. CK2-mediated phosphorylation of occludin S408 facilitates dimerization and diffusion within the membrane, thereby limiting occludin binding to ZO-1 and claudin-2 and allowing flux across claudin-2 pores. Lower panel. CK2 inhibition and occludin dephosphorylation promotes formation of occludin:ZO-1:claudin-2 complexes that reduce claudin-2 anchoring and pore function at the tight junction. (Part B, from Raleigh et al. 2011; reprinted, with permission from The Rockefeller University Press © 2011.)