Based on studies in mice, ROBO1, activated by SLIT1 binding, forms a complex with FLRT3. This interaction involves the intracellular domains of FLRT3 and ROBO1. FLRT3 is a member of the fibronectin leucine-rich repeat transmembrane protein family. The interaction of FLRT3 and ROBO1 in the presence of SLIT1 increases Netrin-1 attraction of thalamocortical axons by increasing the amount of DCC receptors at the plasma membrane via an unknown mechanism that may involve PKA activation (Leyva-Diaz et al. 2014).
The three fibronectin-leucine-rich transmembrane (FLRT) proteins were identified as positive regulators of FGFR signaling that enhance FGFR-dependent RAS/MAPK pathway activation. All three FLRT proteins have been shown to interact with FGFR1 by co-immunoprecipitation and, at least in the case of FLRT3, the interaction is mediated by the FLRT fibronectin-like domain (Bottcher et al, 2004; Haines et al, 2006). Each FLRT gene has a distinct expression pattern and the strength of the protein-protein interaction with the FGF receptor varies, allowing for cell-type specific modulation of signaling activity (Haines et al, 2006). How the FLRT proteins act to enhance FGFR-dependent MAPK pathway activation is not clear, however FLRT1 has recently been shown to be phosphorylated in an FGFR1- and Src family kinase (SFK)-dependent manner (Wheldon et al, 2010).