Protein tyrosine phosphatase ζ (PTPζ) is a receptor type proteins tyrosine phosphatase that uses pleiotrophin like a ligand. plasma membrane of Purkinje cells and Neuro-2A cells and induced their procedure extension. While regular DNER was positively endocytosed and inhibited the retinoic-acid-induced neurite outgrowth of Neuro-2A cells pleiotrophin excitement improved the tyrosine phosphorylation degree of DNER and suppressed the endocytosis of the protein which resulted Ganetespib in the reversal of this Ganetespib inhibition thus allowing neurite extension. These observations suggest that pleiotrophin-PTPζ signaling controls subcellular localization of DNER and thereby regulates neuritogenesis. Protein tyrosine phosphatase ζ (PTPζ) also known as RPTPζ/β 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 (PTPζ-A) the short receptor form (PTPζ-B) and the secreted form (phosphacan) (Fig. ?(Fig.1)1) (28). PTPζ uses two highly related heparin-binding growth factors pleiotrophin (PTN) and midkine as ligands (14 22 29 35 PTN has been shown to suppress the tyrosine phosphatase activity of PTPζ by inducing receptor dimerization (10 29 FIG. 1. Schematic representation of PTPζ and DNER. (A) Structures of PTPζ isoforms are schematically shown. CA carbonic anhydrase-like domain; FN fibronectin type III domain; TM transmembrane segment; D1 and D2 tyrosine phosphatase domains. … PTPζ-PTN signaling has been shown to control neurite extension and cell migration processes probably through the regulation of cytoskeletal dynamics (22 23 31 Ganetespib 32 Although several downstream targets of PTPζ such as β-catenin GIT1/cat-1 and β-adducin have been identified (14 29 33 the regulatory mechanism of neuritogenesis by PTPζ-PTN signaling is largely unknown. We previously demonstrated that PTPζ-PTN signaling is involved in the morphogenesis of cerebellar Purkinje cell dendrites (40 43 By inhibiting the PTPζ-PTN signaling aberrant morphogenesis of Purkinje cell dendrites such as multiple and disoriented primary dendrites was induced in a slice culture system (43). In addition the expression of GLAST a glial glutamate transporter in Bergmann glia was also suppressed by the inhibition of PTPζ signaling (43). Rabbit polyclonal to IL13. During development the dendritic arbors of Purkinje cells elongate in close association with the radial processes of Bergmann glia and the lamellate processes of Bergmann glia also wrap around the cell bodies and dendrites of Purkinje cells suggesting that cell-cell interaction between Ganetespib these cells plays important roles in their development (19 46 Immunohistochemical studies indicated that PTN and phosphacan/PTPζ were deposited in the space between Purkinje cells and the adjacent processes of Bergmann glia which suggested that PTPζ-PTN signaling mediates the interaction between Purkinje cells and Bergmann glia regulating the differentiation of both types of cells (40). On the other hand we recently identified Delta/Notch-like epidermal growth factor (EGF)-related receptor (DNER) (7) a single-pass transmembrane protein with 10 EGF-like repeats in the extracellular domain which is highly expressed in Purkinje cells (Fig. ?(Fig.1).1). DNER acts as a ligand of Notch expressed by Bergmann glia and regulates the development of the cerebellar cortex including the morphogenesis and maturation of Bergmann glia and synapse formation between Purkinje cells and climbing fibers (8 44 Thus DNER-Notch signaling plays critical roles in the Purkinje cell-Bergmann glia interaction. The short cytoplasmic region of DNER contains a tyrosine-based sorting motif YXXΦ (where X and Φ represent any amino acid and a bulky hydrophobic residue respectively) and the C-terminal tail with a dileucine motif. The tyrosine-based motif has been shown to be required for dendritic targeting of DNER from the trans-Golgi network and endocytosis of this protein from the plasma membrane (7). In this study we investigated the possibility that PTPζ regulates the DNER activity by controlling the tyrosine phosphorylation levels of the DNER cytoplasmic domain. We demonstrate here that the tyrosine residues in and adjacent to the sorting motifs of DNER are phosphorylated which leads to the accumulation of this protein on the plasma membrane. Accumulation of DNER on the plasma membrane results in the promotion of neurite expansion. PTPζ affiliates with DNER and may dephosphorylate this receptor increasing the chance that PTPζ-PTN.