Unc5B Interacts with FLRT3 and Rnd1 to Modulate Cell Adhesion in Xenopus Embryos

Abstract

The FLRT family of transmembrane proteins has been implicated in the regulation of FGF signalling, neurite outgrowth, homotypic cell sorting and cadherin-mediated adhesion. In an expression screen we identified the Netrin receptors Unc5B and Unc5D as high-affinity FLRT3 interactors. Upon overexpression, Unc5B phenocopies FLRT3 and both proteins synergize in inducing cell deadhesion in Xenopus embryos. Morpholino knock-downs of Unc5B and FLRT3 synergistically affect Xenopus development and induce morphogenetic defects. The small GTPase Rnd1, which transmits FLRT3 deadhesion activity, physically and functionally interacts with Unc5B, and mediates its effect on cell adhesion. The results suggest that FLRT3, Unc5B and Rnd1 proteins interact to modulate cell adhesion in early Xenopus development.

Unc5D regulates p53-dependent apoptosis in neuroblastoma cells

“…Unc5B and Unc5D were identified to interact with high-affinity fibronectin leucine rich transmembrane protein 3 (FLRT3) (18). FLRT3 and Unc5B functionally interact in modulating cell adhesion during early Xenopus development, and the effect of Unc5B on adhesion is mediated by the Rho family GTPase 1.…”

The fibronectin leucine-rich repeat transmembrane protein Flrt2 is required in the epicardium to promote heart morphogenesis

“…As for other LRR cell-surface molecules, including Toll-TLR receptors, the extracellular LRR domain probably forms a characteristic 'horseshoe'-shaped structure that mediates a wide range of recognition processes (for a review, see Bell et al, 2003;Kobe and Kajava, 2001). Recent evidence suggests that associations between Xenopus Flrt3 or zebrafish Flrt3, Flrt1a and Flrt1b LRR modules, and the Unc5b ectodomain control cell-cell interactions in the developing embryo (Karaulanov et al, 2009;Sollner and Wright, 2009). Interestingly, zebrafish Flrt3, Flrt1a and Flrt1b display a surprising degree of quantitative variation in receptor-binding strength (Sollner and Wright, 2009).…”

“…Interestingly, zebrafish Flrt3, Flrt1a and Flrt1b display a surprising degree of quantitative variation in receptor-binding strength (Sollner and Wright, 2009). Phosphorylation of the Flrt1 cytoplasmic tail has been shown to modulate MAPK activity (Wheldon et al, 2010), whereas the Xflrt3 intracellular region plays a key role in regulating cell de-adhesion during gastrulation via interactions with its cytoplasmic partner, the small GTPase Rnd1 (Ogata et al, 2007;Karaulanov et al, 2009;Chen et al, 2009). This association leads to localized downregulation of C-cadherin to promote cell…”

“…Xenopus Flrt3 and zebrafish Flrt3, Flrt1a and Flrt1b proteins have been shown to interact with Unc5b, a homologue of the netrin receptor (Chen et al, 2009;Karaulanov et al, 2009;Sollner and Wright, 2009). Mouse embryos lacking Unc5b die at around E12.5 due to excessive sprouting within the peripheral capillary network that secondarily causes collapse of the arterial vessels (Lu et al, 2004).…”

Axon Guidance Molecules in Vascular Patterning

“…Cite this article as Cold Spring Harb Perspect Biol 2010;2:a001875 library screening using the FLRT3 ECD (Karaulanov et al 2009). These data suggest that UNC5B has numerous possible interactors/ ligands, and may even have additional, currently unknown binding partners.…”