TBC1d24-ephrinB2 interaction regulates contact inhibition of locomotion in neural crest cell migration

Jaeho Yoon,Ira O Daar,Moonsup Lee,Yoo-Seok Hwang,Jian Sun,Laura Knapik,Hee Jun Cho

doi:10.1038/s41467-018-05924-9

Abstract

Although Eph-ephrin signalling has been implicated in the migration of cranial neural crest (CNC) cells, it is still unclear how ephrinB transduces signals regulating this event. We provide evidence that TBC1d24, a putative Rab35-GTPase activating protein (Rab35 GAP), complexes with ephrinB2 via the scaffold Dishevelled (Dsh) and mediates a signal affecting contact inhibition of locomotion (CIL) in CNC cells. Moreover, we found that, in migrating CNC, the interaction between ephrinB2 and TBC1d24 negatively regulates E-cadherin recycling in these cells via Rab35. Upon engagement of the cognate Eph receptor, ephrinB2 is tyrosine phosphorylated, which disrupts the ephrinB2/Dsh/TBC1d24 complex. The dissolution of this complex leads to increasing E-cadherin levels at the plasma membrane, resulting in loss of CIL and disrupted CNC migration. Our results indicate that TBC1d24 is a critical player in ephrinB2 control of CNC cell migration via CIL.

Highlights

Eph-ephrin signalling has been implicated in the migration of cranial neural crest (CNC) cells, it is still unclear how ephrinB transduces signals regulating this event
Several groups have shown that E-cadherin levels are downregulated to initiate CNC migration, but a low level of E-cadherin is maintained for migrating CNC cells to regulate cell-to-cell adhesion and motility[1,3,21]
We show that the ephrinB2 and TBC1d24 interaction modulates contact inhibition of locomotion (CIL) through regulating E-cadherin recycling

Summary

Introduction

Eph-ephrin signalling has been implicated in the migration of cranial neural crest (CNC) cells, it is still unclear how ephrinB transduces signals regulating this event. Loss-of-function studies targeting Eph–ephrin signalling demonstrate that complementary expression of ephrin ligands and Eph receptors generates bi-directional signalling to modulate repulsion or attraction of migratory CNC cells[22,23,24,25,26,27,28,29,30]. It is still unclear how ephrinB mechanistically transduces the signals affecting this repulsion or attraction. Our results provide the molecular mechanism of how ephrinB2 regulates the CIL response during CNC cell migration

Methods

Results

Conclusion