Receptor Type Protein Tyrosine Phosphatase ζ-Pleiotrophin Signaling Controls Endocytic Trafficking of DNER That Regulates Neuritogenesis

Abstract

Protein tyrosine phosphatase (PTP) is a receptor type protein tyrosine phosphatase that uses pleiotrophin as a ligand. Pleiotrophin inactivates the phosphatase activity of PTP, resulting in the increase of tyrosine phosphorylation levels of its substrates. We studied the functional interaction between PTP and DNER, a Notch-related transmembrane protein highly expressed in cerebellar Purkinje cells. PTP and DNER displayed patchy colocalization in the dendrites of Purkinje cells, and immunoprecipitation experiments indicated that these proteins formed complexes. Several tyrosine residues in and adjacent to the tyrosine-based and the second C-terminal sorting motifs of DNER were phosphorylated and were dephosphorylated by PTP, and phosphorylation of these tyrosine residues resulted in the accumulation of DNER on the plasma membrane. DNER mutants lacking sorting motifs accumulated on the plasma membrane of Purkinje cells and Neuro-2A cells and induced their process extension. While normal DNER was actively endocytosed and inhibited the retinoic-acid-induced neurite outgrowth of Neuro-2A cells, pleiotrophin stimulation increased the tyrosine phosphorylation level of DNER and suppressed the endocytosis of this protein, which led to the reversal of this inhibition, thus allowing neurite extension. These observations suggest that pleiotrophin-PTP signaling controls subcellular localization of DNER and thereby regulates neuritogenesis.Protein tyrosine phosphatase (PTP), also known as RPTP/␤, is a receptor type protein tyrosine phosphatase that is synthesized as a chondroitin sulfate proteoglycan (12,16,17,21,28,32). There are three major splice variants of this molecule, the full-length form (PTP-A), the short receptor form (PTP-B), and the secreted form (phosphacan) (Fig.

Delta/Notch-Like EGF-Related Receptor (DNER) is Expressed in Hair Cells and Neurons in the Developing and Adult Mouse Inner Ear

“…Nevertheless, the robust expression of this molecule suggests that there may be other roles for DNER that eluded our analysis. Interestingly, DNER was recently shown to be actively endocytosed by a protein tyrosine phosphatase and inhibit neurite outgrowth in Neuro-2A cells (Fukazawa et al 2008) …”

Receptor-type Protein-tyrosine Phosphatase ζ Is a Functional Receptor for Interleukin-34

“…2F). (57) and neuritogenesis (58) in mouse and in the in vitro and in vivo growth of human glioblastomas (40,59,60). As previous studies have shown that PTN inhibits the growth of glioblastomas, to determine the functional relevance of PTP-receptor engagement by IL-34, we tested the effects of IL-34 and PTN on the U251 glioblastoma cells expressing either PTP-or scrambled (control) shRNA.…”

Functional Receptors and Intracellular Signal Pathways of Midkine (MK) and Pleiotrophin (PTN)

“…78) Delta/Notch-like epidermal growth factor (EGF)-related receptor (DNER) is a transmembrane protein highly expressed in cerebellar Purkinje cells along with co-localization of RPTPζ. 79) Normal DNER is endocytosed and inhibits the retinoic-acid-induced neurite outgrowth of Neuro-2A cells. PTN stimulation inhibits the RPTPζ phosphatase activity and increases the tyrosine phosphorylation level of DNER and suppresses the endocytosis of this protein.…”

“…PTN stimulation inhibits the RPTPζ phosphatase activity and increases the tyrosine phosphorylation level of DNER and suppresses the endocytosis of this protein. 79) Phosphorylated DNER accumulates on the plasma membrane and induces neurite outgrowth, probably though Notch signal pathway which has important roles in cell-cell adhesion and cell differentiation. 79) Fyn is a tyrosine kinase belonging to the Src family and involves in the cell plasticity, cell-cell adhesion, cell migration and cell proliferation.…”

“…79) Phosphorylated DNER accumulates on the plasma membrane and induces neurite outgrowth, probably though Notch signal pathway which has important roles in cell-cell adhesion and cell differentiation. 79) Fyn is a tyrosine kinase belonging to the Src family and involves in the cell plasticity, cell-cell adhesion, cell migration and cell proliferation. Fyn interacts with the intracellular active site of RPTPζ, and its tyrosine phosphorylation level increases as soon as PTN stimulates.…”