IQGAP1 Controls Tight Junction Formation Through Differential Regulation of Claudin Recruitment

Abstract

IQGAP1 is a scaffolding protein previously implicated in adherens junction formation. However, its role in the establishment or maintenance of tight junctions (TJs) has not been explored. We hypothesized that IQGAP1 could regulate TJ formation by modulating the expression and/or localization of junctional proteins, and we systematically tested this hypothesis in the model Madin-Darby canine kidney (MDCK) cell line. We find that IQGAP1 silencing enhances a transient increase in transepithelial electrical resistance (TER) observed during the early stages of TJ formation (Cereijido et al., 1978). Quantitative microscopy and biochemical experiments suggest that this effect of IQGAP1 on TJ assembly is accounted for by reduced expression and TJ recruitment of claudin 2, and increased TJ recruitment of claudin 4. Furthermore, we show that IQGAP1 also regulates TJ formation through its interactor CDC42, because IQGAP1 knockdown increases the activity of the CDC42 effector JNK and dominantnegative CDC42 prevents the increase in TER caused by IQGAP1 silencing. Hence, we provide evidence that IQGAP1 modulates TJ formation by a twofold mechanism: (1) controlling the expression and recruitment of claudin 2 and recruitment of claudin 4 to the TJ, and (2) transient inhibition of the CDC42-JNK pathway.

Multiple roles for keratin intermediate filaments in the regulation of epithelial barrier function and apico-basal polarity

“…That is the case of aPKC in the PAR “polarity complex.” 65-67 Likewise, ERK1/2 controls expression of TJ proteins, 68 and junction formation 69,70 . Furthermore, JNK has been shown to be part of a pathway that modulates trans-epithelial resistance 71 and ZO-1 assembly 72 . Loss of K76 results in increased skin permeability via loss of claudin 1 73 .…”

Simvastatin preparations promote PDGF‐BB secretion to repair LPS‐induced endothelial injury through the PDGFRβ/PI3K/Akt/IQGAP1 signalling pathway

“…In addition, our study showed that cell junctions involving VE‐cadherin and claudin‐5 are altered after IQGAP1 treatment during the processes of endothelial cell injury to recovery. Furthermore, previous studies showed that IQGAP1 mediates barrier function changes by regulating the tight junctions and adherens junctions of endothelial cells . Some studies reported that after the knockdown of IQGAP1, the morphology and function of vascular endothelial cells were altered, indicating that a decrease in IQGAP1 was the cause of endothelial barrier dysfunction .…”

“…The Imatinib has no significant effect on TEER, monolayer permeability, cell migration and PDGFRβ/PI3K/Akt/IQGAP1 pathway activity of HUVECs (Figure S1 regulating the tight junctions and adherens junctions of endothelial cells. [46][47][48][49] Some studies reported that after the knockdown of IQGAP1, the morphology and function of vascular endothelial cells were altered, indicating that a decrease in IQGAP1 was the cause of endothelial barrier dysfunction. 11 Similarly, we found that SV/ SV-NPs up-regulated the expression of IQGAP1.…”

The Roles of RNase-L in Antimicrobial Immunity and the Cytoskeleton-Associated Innate Response

“…IQGAP1 alters TJ assembly by reducing the recruitment of claudin 2 and increasing the assembly of claudin 4 into TJ complexes. It also diminishes barrier function by inhibiting the Cdc42-JNK signaling pathway [ 115 ]. Conversely, RNase-L promotes the expression of TJ proteins claudin 1 and occludin, enhances barrier function, and prevents the transepithelial migration of pathogens such as EPEC [ 84 ].…”