Abstract
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.
Highlights
Protein phosphorylation is one of the most common post-translational modifications used by eukaryotic cells to regulate various aspects of protein function
We propose that Density-Enhanced Phosphatase-1 (DEP-1) regulates Epidermal Growth Factor Receptor (EGFR) signaling via two parallel mechanisms, by direct receptor de-phosphorylation and by restricting receptor mobility through αβ-integrin activation
41 peptides were from NID-1 (MW = 174.4 kD), an extracellular matrix (ECM) component that interacts with the extracellular domain of integrins [24]
Summary
Protein phosphorylation is one of the most common post-translational modifications used by eukaryotic cells to regulate various aspects of protein function. Signaling through the conserved Epidermal Growth Factor Receptor (EGFR) pathway involves receptor auto-phosphorylation as well as the phosphorylation of several downstream signal transduction molecules once an EGF ligand has bound to and activated the receptor tyrosine kinase [1]. The Density Enhanced Phosphatase DEP-1, known as PTPRJ, PTP-η or CD148, belongs to the class III Receptor Protein Tyrosine Phosphatase (R-PTP) family [4,5]. A multitude of potential DEP-1 substrates have been identified, including various growth factor receptors such as EGFR, PDGFR, VEGFR, FLT-3, MET, the ERK-2 kinase, the p85 subunit of PI3K as well as cell-cell junction proteins like p120ctn, β-catenin and γ-catenin, occludin and ZO-1 [4,11,12]
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