Modulation of Tight Junction Structure and Function by Kinases and Phosphatases Targeting Occludin

Abstract

Tight junctions (TJs) typically represent the most apical contacts in epithelial and endothelial cell layers where they play an essential role in the separation of extracellular or luminal spaces from underlying tissues in the body. Depending on the protein composition, TJs define the barrier characteristics and in addition maintain cell polarity. Two major families of integral membrane proteins form the typical TJ strand network, the tight junction-associated MARVEL protein (TAMP) family members occludin, tricellulin, and MarvelD3 as well as a specific set of claudins. Occludin was the first identified member of these tetraspanins and is now widely accepted as a regulator of TJ assembly and function. Therefore, occludin itself has to be tightly regulated. Phosphorylation of occludin appears to be of central importance in this context. Here we want to summarize current knowledge on the kinases and phosphatases directly modifying occludin, and their role in the regulation of TJ structure, function, and dynamics.

The zinc sensing receptor, ZnR/GPR39, triggers metabotropic calcium signalling in colonocytes and regulates occludin recovery in experimental colitis

“…Importantly, the intracellular Ca 2þ response was also abolished when ZnR/GPR39 was silenced using an siRNA construct (figure 1d), indicating that it is directly mediated by ZnR/GPR39. To determine a physiological role for ZnR/GPR39-dependent Ca 2þ signalling, we asked whether ZnR/GPR39 regulates the expression of occludin, an important factor of the tight junction barrier in the colon [3]. Indeed, silencing of ZnR/GPR39 in Caco-2 cells largely downregulated occludin expression (figure 1e).…”

“…Tight junctions connect the epithelial cells, and induce a continuous boundary between the lumen and the mucosal layer thereby protecting from paracellular permeation and subsequent inflammation. Occludin is a critical component of the tight junction complexes but its localization to the apical cell surface may be disrupted by pathological stimuli [3,4]. Although mechanisms underlying IBD are not fully understood, breakdown of the physical epithelial tight junction barrier often precedes the onset of inflammation.…”

In tight junctions, claudins regulate the interactions between occludin, tricellulin and marvelD3, which, inversely, modulate claudin oligomerization

“…Its C-terminus contains a coiled coil domain which is involved in a redox-sensitive dimerization of Occl (Walter et al, 2009) and in the association of zonula occludens protein 1 (ZO-1) (Müller et al, 2005). Occl is phosphorylated by different protein kinases on serine, threonine and tyrosine residues (for a review, see Dörfel and Huber, 2012). Typical kinases are conventional Ca 2+ dependent and novel diacylglycerol dependent kinases (Andreeva et al, 2006), CK1, CK2 (Dörfel et al, 2009), c-Src (Kale et al, 2003), c-Yes (Chen et al, 2002) and activated, phosphorylated ERK 1 (extracellular signal related kinase) (Basuroy et al, 2006).…”

Exercise regulation of intestinal tight junction proteins

“…Both TJ and the apical membrane of enterocytes constitute the intestinal barrier,3 which allows absorption of nutrients and water4 while also preventing the translocation of harmful substances from the gut to the bloodstream 1. The integrity of the intestinal barrier is regulated by the phosphorylation state of the TJ proteins where the type of kinase and binding site play a role 5 6…”