On 8 Jun.2020, Guangshuo Ou's group published 'Spatial Confinement of Receptor Activity by Tyrosine Phosphatase During Directional Cell Migration' in PNAS.
A fundamental but unresolved question in directional cell migration is how a migrating cell forms only one leading edge. Here we study the activation and inhibition of an evolutionarily conserved MIG-13/LRP12-Arp2/3 signaling pathway that guides Caenorhabditis elegans neuroblast migration. We show that a tyrosine kinase SRC-1 directly phosphorylates MIG-13 and promotes its activity on actin assembly at the leading edge. SRC-1 and MIG-13 distribute along the entire plasma membrane, and a receptor-like tyrosine phosphatase, PTP-3, dephosphorylates SRC-1–dependent MIG-13 phosphorylation and accumulates at the rear to prevent ectopic actin polymerization. We discover that the asymmetrically localized tyrosine phosphatase spatially restricts receptor activity, thereby inhibiting ectopic polarization and secondary fronts in migrating cells.
Directional cell migration involves signaling cascades that stimulate actin assembly at the leading edge, and additional pathways must inhibit actin polymerization at the rear. During neuroblast migration in Caenorhabditis elegans, the transmembrane protein MIG-13/Lrp12 acts through the Arp2/3 nucleation-promoting factors WAVE and WASP to guide the anterior migration. Here we show that a tyrosine kinase, SRC-1, directly phosphorylates MIG-13 and promotes its activity on actin assembly at the leading edge. In GFP knockin animals, SRC-1 and MIG-13 distribute along the entire plasma membrane of migrating cells. We reveal that a receptor-like tyrosine phosphatase, PTP-3, maintains the F-actin polarity during neuroblast migration. Recombinant PTP-3 dephosphorylates SRC-1–dependent MIG-13 phosphorylation in vitro. Importantly, the endogenous PTP-3 accumulates at the rear of the migrating neuroblast, and its extracellular domain is essential for directional cell migration. We provide evidence that the asymmetrically localized tyrosine phosphatase PTP-3 spatially restricts MIG-13/Lrp12 receptor activity in migrating cells.