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N-cadherin-regulated FGFR ubiquitination and degradation control mammalian neocortical projection neuron migration.

ABSTRACT: The functions of FGF receptors (FGFRs) in early development of the cerebral cortex are well established. Their functions in the migration of neocortical projection neurons, however, are unclear. We have found that FGFRs regulate multipolar neuron orientation and the morphological change into bipolar cells necessary to enter the cortical plate. Mechanistically, our results suggest that FGFRs are activated by N-Cadherin. N-Cadherin cell-autonomously binds FGFRs and inhibits FGFR K27- and K29-linked polyubiquitination and lysosomal degradation. Accordingly, FGFRs accumulate and stimulate prolonged Erk1/2 phosphorylation. Neurons inhibited for Erk1/2 are stalled in the multipolar zone. Moreover, Reelin, a secreted protein regulating neuronal positioning, prevents FGFR degradation through N-Cadherin, causing Erk1/2 phosphorylation. These findings reveal novel functions for FGFRs in cortical projection neuron migration, suggest a physiological role for FGFR and N-Cadherin interaction in vivo and identify Reelin as an extracellular upstream regulator and Erk1/2 as downstream effectors of FGFRs during neuron migration.

SUBMITTER: Kon E

PROVIDER: S-EPMC6786859 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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N-cadherin-regulated FGFR ubiquitination and degradation control mammalian neocortical projection neuron migration.

Kon Elif E Calvo-Jiménez Elisa E Cossard Alexia A Na Youn Y Cooper Jonathan A JA Jossin Yves Y

eLife 20191002

The functions of FGF receptors (FGFRs) in early development of the cerebral cortex are well established. Their functions in the migration of neocortical projection neurons, however, are unclear. We have found that FGFRs regulate multipolar neuron orientation and the morphological change into bipolar cells necessary to enter the cortical plate. Mechanistically, our results suggest that FGFRs are activated by N-Cadherin. N-Cadherin cell-autonomously binds FGFRs and inhibits FGFR K27- and K29-linke ...[more]

PMID: 31577229

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Project description:Hepatocytes are epithelial cells with highly specialized polarity. The disorder and loss of hepatocyte polarity leads to a weakness of cell adhesion and connection, the induction of epithelial-mesenchymal transition, and eventually the occurrence of hepatocellular carcinoma (HCC). Cluster of differentiation 147 (CD147), a tumor-related glycoprotein, promotes epithelial-mesenchymal transition and the invasion of HCC. However, the function of CD147 in hepatocyte depolarization is unknown. Here we identified that CD147 was basolaterally polarized in hepatocyte membrane of liver tissues and HepG2 cells. CD147 not only promoted transforming growth factor-?1-mediated hepatocyte polarity loss but also directly induced endocytosis and down-regulation of E-cadherin which contributed to hepatocyte depolarization. Overexpression of CD147 induced Src activation and subsequently recruited ubiquitin ligase Hakai for E-cadherin ubiquitination and lysosomal degradation, leading to decreases of partitioning defective 3 expression and ?-catenin nuclear translocation. This signal transduction was initiated by competitive binding of CD147 with integrin ?1 that interrupted the interaction between the Arg-Gly-Asp motif of fibronectin and integrin ?1. The specific antibodies targeting integrin ?5 and ?1 reversed the decrease of E-cadherin and partitioning defective 3 levels induced by CD147 overexpression. In human liver tissues, CD147 polarity rates significantly declined from liver cirrhosis (71.4%) to HCC (10.4%). CD147-polarized localization negatively correlated with Child-Pugh scores in human liver cirrhosis (r = -0.6092, P < 0.0001) and positively correlated with differentiation grades in HCC (r = 0.2060, P = 0.004). HCC patients with CD147-polarized localization had significantly better overall survival than patients with CD147 nonpolarity (P = 0.021). CONCLUSION:The ectopic CD147-polarized distribution on basolateral membrane promotes hepatocyte depolarization by activation of the CD147-integrin ?5?1-E-cadherin ubiquitination-partitioning defective 3 decrease and ?-catenin translocation signaling cascade, replenishing a molecular pathway in hepatic carcinogenesis. (Hepatology 2018;68:317-332).

Dataset Information

N-cadherin-regulated FGFR ubiquitination and degradation control mammalian neocortical projection neuron migration.

Publications

N-cadherin-regulated FGFR ubiquitination and degradation control mammalian neocortical projection neuron migration.

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