Functional Roles of Protein Tyrosine Phosphatase zeta(PTP zeta/RPTPß)

 Protein tyrosine phosphatase zeta (PTP zeta/RPTPß) is a receptor-like protein-tyrosine phosphatase, which is mainly expressed in the central nervous system. PTP zeta is composed of an N-terminal carbonic anlydrase-like domain, a fibronectin type III domain, a serine, glycine-rich domain, a transmembrane segment, and two tyrosine phosphatase domains (Figure). There exist three RNA-splicing variants of this molecule: the full-length PTPzeta (PTP zeta-A); the short form of PTP zeta (PTP zeta-B), in which most of the serine, glycine-rich region is deleted, and the secreted form (PTP zeta-S), which corresponds to the extracellular region of PTP zeta-A and is also known as phosphacan/6B4 proteoglycan/DSD-1-PG. All these splice variants are expressed as chondroitin sulfate proteoglycans in the brain (1). In addition, PTP zeta-A and -S are spatiotemporally modified with keratan sulfate in the developing brain. PTPgamma and its splicing variants, a receptor-like PTP which is structurally related to PTP zeta and has also similar splicing variants, are not proteoglycans.

PTP zeta is continuously expressed from the early embryonic stage to adulthood. In the postnatal brain, subsets of neurons as well as astrocytes express PTP zeta. This suggests that PTP zeta plays variegated roles, such as cell migration, axonal elongation, synapse formation, and synaptic regulation in the developing and matured brain. It is known that the extracellular domain of PTP zeta binds various extracellular matrix proteins (tenascin-C and -R), growth factors (pleiotrophin/heparin-binding growth-associated molecule (HB-GAM), midkine, and fibroblast growth factor-2 (FGF-2)) and cell-adhesion molecules (Nr-CAM, L1/Ng-CAM, F3/contactin, N-CAM, and TAG-1/axonin-1) (2). The binding to cell-adhesion molecules suggests the possibility that PTP zeta functions bidirectionally between cells not only as a receptor but also as a ligand (3). PTP zeta is believed to be intrinsically active from the analogy of other RPTPs.

As for substrate molecules for PTP zeta, only two molecules, ß-catenin and brain sodium channel II, have been reported to date. Experimental data indicate that pleiotrophin increased tyrosine-phosphorylation level of ß-catenin through ligand-dependent receptor inactivation of PTP zeta (4). This explains the finding that pleiotrophin stimulates neuronal migration through PTP zeta. Recently, it was also revealed that PTP zeta interacts with PSD-95/SAP90 family members, SAP102, PSD95/SAP90, and SAP97/hDlg, which are concentrated in the central synapses mediating protein-protein interactions to form a large synaptic macromolecular complex including neurotransmitter receptors and ionic channels (5). Here, C-terminus of PTP zeta binds to PSD-95/SAP90 proteins through the second PDZ domain. This suggests the possibility that PTP zeta is also involved in the regulation of synapse formation and synaptic transmission.

Masaharu Noda (Division of Molecular Neurobiology,
National Insttitute for Basic Biology)
References(1) Nishiwaki, T., Maeda, N. and Noda, M.: Characterization and developmental regulation of proteoglycan-type protein tyrosine phosphatase zeta/RPTPß isoforms. J. Biochem. 123: 458-467, 1998
(2) Maeda, N., Nishiwaki, T., Shintani, T., Hamanaka, H. and Noda, M.: 6B4 proteoglycan/phosphacan, an extracellular variant of receptor-like protein-tyrosine phosphatase zeta/RPTPß, binds pleiotrophin/HB-GAM. J. Biol. Chem. 271: 21446-21452, 1996
(3) Peles, E., Nativ, M., Lustig, M., Grumet, M., Schilling, J., Martinez, R., Plowman, G. D. and Schlessinger, J. Identification of a novel contactin-associated transmembrane receptor with multiple domains implicated in protein-protein interactions. EMBO J. 16: 978-988, 1997
(4) Meng, K., Rodrigues-PenA., Dimitrov, T., Chen, W., Yamin, M., Noda, M. and Deuel, T. F. Pleiotrophin signals increased tyrosine phosphorylation of ß-catenin through inactivation of the intrinsic catalytic activity of the receptor-type protein tyrosine phosphatase ß /zeta. Proc. Natl. Acad. Sci. USA 97: 2603-2608, 2000
(5) Kawachi, H., Tamura, H., Watakabe, I., Shintani, T., Maeda, N. and Noda, M. Protein tyrosine phosphatase zeta/RPTPß interacts with PSD-95/SAP90 family. Mol. Brain Res. 72: 47-54, 1999
Links PG-C03 Involvement of Protein Tyrosine Phosphatase Receptor Type Z (Ptprz/PTP/RPTPß) Signaling in Gastric Ulcer Induction by VacA of Helicobacter Pylori (Masaharu Noda)
Mar. 15, 2001

GlycoscienceNow INDEXReturn to Top Page