β-Integrin de-phosphorylation by the Density-Enhanced Phosphatase DEP-1 attenuates EGFR signaling in C. elegans

Density-enhanced phosphatase-1 (dep-1) de-phosphorylates various growth factor receptors and adhesion proteins to regulate cell proliferation,adhesion and migration. moreover,dep-1/scc1 mutations have been detected in various types of human cancers,indicating a broad tumor suppressor activity. during c. elegans development,dep-1 mediates binary cell fate decisions by negatively regulating egfr signaling. using a substrate-trapping dep-1 mutant in a proteomics approach,we have identified the c. elegans β-integrin subunit pat-3 as a specific dep-1 substrate. dep-1 selectively de-phosphorylates tyrosine 792 in the membrane-proximal npxy motif to promote integrin activation via talin recruitment. the non-phosphorylatable β-integrin mutant pat-3(y792f) partially suppresses the hyperactive egfr signaling phenotype caused by loss of dep-1 function. thus,dep-1 attenuates egfr signaling in part by de-phosphorylating y792 in the β-integrin cytoplasmic tail,besides the direct de-phosphorylation of the egfr. furthermore,in vivo frap analysis indicates that the αβ-integrin/talin complex attenuates egfr signaling by restricting receptor mobility on the basolateral plasma membrane. we propose that dep-1 regulates egfr signaling via two parallel mechanisms,by direct receptor de-phosphorylation and by restricting receptor mobility through αβ-integrin activation. © 2017 walser et al.