The Rac activator Tiam1 controls tight junction biogenesis in keratinocytes through binding to and activation of the Par polarity complex

Abstract

The GTPases Rac and Cdc42 play a pivotal role in the establishment of cell polarity by stimulating biogenesis of tight junctions (TJs). In this study, we show that the Rac-specific guanine nucleotide exchange factor Tiam1 (T-lymphoma invasion and metastasis) controls the cell polarity of epidermal keratinocytes. Similar to wild-type (WT) keratinocytes, Tiam1-deficient cells establish primordial E-cadherin–based adhesions, but subsequent junction maturation and membrane sealing are severely impaired. Tiam1 and V12Rac1 can rescue the TJ maturation defect in Tiam1-deficient cells, indicating that this defect is the result of impaired Tiam1–Rac signaling. Tiam1 interacts with Par3 and aPKCζ, which are two components of the conserved Par3–Par6–aPKC polarity complex, and triggers biogenesis of the TJ through the activation of Rac and aPKCζ, which is independent of Cdc42. Rac is activated upon the formation of primordial adhesions (PAs) in WT but not in Tiam1-deficient cells. Our data indicate that Tiam1-mediated activation of Rac in PAs controls TJ biogenesis and polarity in epithelial cells by association with and activation of the Par3–Par6–aPKC polarity complex.

Uterine RAC1 via Pak1-ERM signaling directs normal luminal epithelial integrity conducive to on-time embryo implantation in mice

“…20 GTP-bounded active Rac1 is also necessary for the activation of Parcomplex-associated signaling to initiate tight junction morphogenesis and epithelial polarization. 50,51 In line with these previous observations, we also found that the length of Rac1 d/d epithelium from basal to apical membrane is shorter, and the apical membrane is obviously more flat compared with the Rac1 f/f epithelium. Furthermore, the tight junction molecules Par3, Occludin and Claudin 7 are remarkably decreased in the apical membrane of Rac1 d/d luminal epithelium.…”

Rac1 is crucial for Ras-dependent skin tumor formation by controlling Pak1-Mek-Erk hyperactivation and hyperproliferation in vivo

“…It was reported earlier that inhibition of Rac1 increased apoptosis of primary keratinocytes under starving conditions in vitro (Mertens et al, 2005). In vivo, however, we did not detect increased apoptosis in Rac1-deficient keratinocytes, neither in DMBA/TPAtreated nor in untreated mice.…”

“…Rac1, therefore, is essential for DMBA/TPAinduced keratinocyte hyperproliferation in vivo, although it is not required for proliferation under physiological conditions. Studies with mice lacking the Rac1-activating molecule Tiam1 in keratinocytes showed that reduced Rac1 activity promotes keratinocyte apoptosis in serum-free conditions (Mertens et al, 2005). In DMBA/TPAtreated epidermis, we detected an increase of cleaved caspase 3 þ apoptotic cells, but no difference between control and Rac1-deficient skin (Figures 1d and e).…”

Regulation of lung endoderm progenitor cell behavior by miR302/367

“…Examination of the potential target list for miR302/367 revealed Tiam1 and Lis1 as predicted targets of miR302/367 (see Table S2 in the supplementary material). The Rac activator Tiam1, a T-lymphoma invasion and metastasis-inducing protein, acts as a crucial component of the Par complex in regulating neuronal and epithelial apical-basal polarity (Chen and Macara, 2005;Mertens et al, 2005;Nishimura et al, 2005). Lis1 (-subunit of plateletactivating factor acetylhydrolase) is essential for proliferation and the precise control of mitotic spindle orientation in both neuroepithelial stem cells and radial glial progenitor cells (Yingling et al, 2008;Yamada et al, 2010).…”