Fbxo45 Binds SPRY Motifs in the Extracellular Domain of N-Cadherin and Regulates Neuron Migration during Brain Development

Abstract

Several events during the normal development of the mammalian neocortex depend on N-cadherin, including the radial migration of immature projection neurons into the cortical plate. Remarkably, radial migration requires the N-cadherin extracellular domain but not N-cadherin-dependent homophilic cell-cell adhesion, suggesting that other N-cadherin-binding proteins may be involved. We used proximity ligation and affinity purification proteomics to identify N-cadherin-binding proteins. Both screens detected MycBP2 and SPRY domain protein Fbxo45, two components of an intracellular E3 ubiquitin ligase. Fbxo45 appears to be secreted by a nonclassical mechanism, not involving a signal peptide and not requiring transport from the endoplasmic reticulum to the Golgi apparatus. Fbxo45 binding requires N-cadherin SPRY motifs that are not involved in cell-cell adhesion. SPRY mutant N-cadherin does not support radial migration in vivo. Radial migration was similarly inhibited when Fbxo45 expression was suppressed. The results suggest that projection neuron migration requires both Fbxo45 and the binding of Fbxo45 or another protein to SPRY motifs in the extracellular domain of N-cadherin.

Reelin Functions, Mechanisms of Action and Signaling Pathways During Brain Development and Maturation

“…Differences in protocols, timing of stimulation, concentration of Reelin or the background of mice could result in different levels of stimulation. The F-box protein Fbxo45 is secreted by an unconventional mechanism by cortical neurons and interacts with the extracellular domain of N-cadherin [ 164 ]. This interaction seems to be important for N-cadherin functions during multipolar migration, but the mechanism of action is still unclear.…”

Fbxo45‐mediated NP‐STEP46 degradation via K6‐linked ubiquitination sustains ERK activity in lung cancer

“…4C ). In the structure of Fbxo45, the SPRY domain is supposed to be in charge of recognizing the specific substrates [ 34 , 35 , 41 ]. In line with that, the co‐immunoprecipitation assay revealed that Fbxo45 without SPRY domain (i.e., Fbxo45ΔSPRY) lost the ability of binding to STEP 46 protein (Fig.…”

Fbxo45 facilitates pancreatic carcinoma progression by targeting USP49 for ubiquitination and degradation

“…Recently, another study demonstrated that DNAJB9 blocked the tumor metastasis by enhancing Fbxo45-involved degradation of ZEB1 in TNBC cells [ 31 ]. Two groups reported that Fbxo45 can bind to and degrade N-cadherin and regulate neuron migration to affect neuronal differentiation and brain development [ 32 , 33 ]. Consistently, our study also showed that Fbxo45 can regulate the expression of Zeb1 and N-cadherin in pancreatic cancer cells.…”