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PLoS One 2017 Nov 30;1211:e0188963. doi: 10.1371/journal.pone.0188963.
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The ectodomain of cadherin-11 binds to erbB2 and stimulates Akt phosphorylation to promote cranial neural crest cell migration.

Mathavan K , Khedgikar V , Bartolo V , Alfandari D .

During development, a multi-potent group of cells known as the cranial neural crest (CNC) migrate to form craniofacial structures. Proper migration of these cells requires proteolysis of cell adhesion molecules, such as cadherins. In Xenopus laevis, preventing extracellular cleavage of cadherin-11 impairs CNC migration. However, overexpression of the soluble cleavage product (EC1-3) is capable of rescuing this phenotype. The mechanism by which EC1-3 promotes CNC migration has not been investigated until now. Here we show that EC1-3 stimulates phosphorylation of Akt, a target of PI3K, in X.laevis CNC. Through immunoprecipitation experiments, we determined that EC1-3 interacts with all ErbB receptors, PDGFRα, and FGFR1. Of these receptors, only ErbB2 was able to produce an increase in Akt phosphorylation upon treatment with a recombinant EC1-3. This increase was abrogated by mubritinib, an inhibitor of ErbB2. We were able to recapitulate this decrease in Akt phosphorylation in vivo by knocking down ErbB2 in CNC cells. Knockdown of the receptor also significantly reduced CNC migration in vivo. We confirmed the importance of ErbB2 and ErbB receptor signaling in CNC migration using mubritinib and canertinib, respectively. Mubritinib and the PI3K inhibitor LY294002 significantly decreased cell migration while canertinib nearly prevented it altogether. These data show that ErbB2 and Akt are important for CNC migration and implicate other ErbB receptors and Akt-independent signaling pathways. Our findings provide the first example of a functional interaction between the extracellular domain of a type II classical cadherin and growth factor receptors.

PubMed ID: 29190819
PMC ID: PMC5708760
Article link: PLoS One

Species referenced: Xenopus laevis
Genes referenced: adam13 akt1 akt2 arhgef7 arid3a cdh11 egfr erbb2 erbb3 erbb4 fgfr1 fn1 mapk1 myc pik3ca pik3cg snai2 sox10 twist1
GO keywords: neural crest cell migration
Antibodies: Akt Ab11 Akt Ab9 mapk1 Ab17
Morpholinos: erbb2 MO1

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References [+] :
Abbruzzese, The Wnt receptor Frizzled-4 modulates ADAM13 metalloprotease activity. 2015, Pubmed, Xenbase