Abstract
In common with other p120-catenin subfamily members, Xenopus ARVCF (xARVCF) binds cadherin cytoplasmic domains to enhance cadherin metabolic stability or, when dissociated, modulates Rho-family GTPases. We report here that xARVCF binds and is stabilized by Xenopus KazrinA (xKazrinA), a widely expressed conserved protein that bears little homology to established protein families, and which is known to influence keratinocyte proliferation and differentiation and cytoskeletal activity. Although we found that xKazrinA binds directly to xARVCF, we did not resolve xKazrinA within a larger ternary complex with cadherin, nor did it co-precipitate with core desmosomal components. Instead, screening revealed that xKazrinA binds spectrin, suggesting a potential means by which xKazrinA localizes to cell-cell borders. This was supported by the resolution of a ternary biochemical complex of xARVCF-xKazrinA-xβ2-spectrin and, in vivo, by the finding that ectodermal shedding followed depletion of xKazrin in Xenopus embryos, a phenotype partially rescued with exogenous xARVCF. Cell shedding appeared to be the consequence of RhoA activation, and thereby altered actin organization and cadherin function. Indeed, we also revealed that xKazrinA binds p190B RhoGAP, which was likewise capable of rescuing Kazrin depletion. Finally, xKazrinA was found to associate with δ-catenins and p0071-catenins but not with p120-catenin, suggesting that Kazrin interacts selectively with additional members of the p120-catenin subfamily. Taken together, our study supports the essential role of Kazrin in development, and reveals the biochemical and functional association of KazrinA with ARVCF-catenin, spectrin and p190B RhoGAP.
Highlights
Catenins were initially defined as molecules that bind cadherins (Ozawa et al, 1989) and, with the exception of -catenin, that possess a central Armadillo (Arm) domain that mediates cadherin and other protein–protein interactions (Choi and Weis, 2005; Huber et al, 1997; Peifer et al, 1994)
We found that xKazrinA interacts directly with Xenopus Armadillo-repeat protein deleted in velo-cardio-facial syndrome (ARVCF) (xARVCF) but not with Xenopus laevis p120 (Xp120) or -catenin, and as reported earlier is present at cell–cell junctions (Groot et al, 2004)
We propose that xKazrinA enables xARVCF association with the spectrin–actin network, and that the xARVCF–xKazrinA–Xp190B complex modulates RhoA activity and thereby cytoskeletal organization, cell adhesion and ectodermal integrity
Summary
Catenins were initially defined as molecules that bind cadherins (Ozawa et al, 1989) and, with the exception of -catenin, that possess a central Armadillo (Arm) domain that mediates cadherin and other protein–protein interactions (Choi and Weis, 2005; Huber et al, 1997; Peifer et al, 1994). Members of the p120-catenin subfamily, such as p120-catenin, Armadillo-repeat protein deleted in velo-cardio-facial syndrome (ARVCF)-catenin and -catenin, modulate cadherin stability at cell–cell junctions (Davis et al, 2003; Fang et al, 2004; Gu et al, 2009; Ireton et al, 2002; Xiao et al, 2003). They directly or indirectly associate with and regulate small GTPases, enabling intracellular signaling and cytoskeletal control (for a review, see Anastasiadis, 2007). In comparison to -catenin and p120-catenin, relatively little is known concerning the interactions and functional roles of ARVCF-catenin or other catenins
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