Receptor Protein Tyrosine Phosphatases in Nervous System Development

Abstract

Receptor protein tyrosine phosphatases (RPTPs) are key regulators of neuronal morphogenesis in a variety of different vertebrate and invertebrate systems, yet the mechanisms by which these proteins regulate central nervous system development are poorly understood. In the past few years, studies have begun to outline possible models for RPTP function by demonstrating in vivo roles for RPTPs in axon outgrowth, guidance, and synaptogenesis. In addition, the crystal structures of several RPTPs have been solved, numerous downstream effectors of RPTP signaling have been identified, and a small number of RPTP ligands have been described. In this review, we focus on how RPTPs transduce signals from the extracellular environment to the cytoplasm, using a detailed comparative analysis of the different RPTP subfamilies. Focusing on the roles RPTPs play in the development of the central nervous system, we discuss how the elucidation of RPTP crystal structures, the biochemical analysis of phosphatase enzyme catalysis, and the characterization of complex signal transduction cascades downstream of RPTPs have generated testable models of RPTP structure and function.

The protein tyrosine phosphatases PTPRZ and PTPRG bind to distinct members of the contactin family of neural recognition molecules

“…The receptor protein tyrosine phosphatases (RPTPs) participate in these two seemingly disparate processes as they combine extracellular domains (ECDs) that resemble those of cell adhesion molecules (CAMs) with one or two intracellular tyrosine phosphatase domains (1). In particular, the proteins PTPRG and PTPRZ make up the type V subgroup of RPTPs and are expressed predominantly in the developing and adult brains of vertebrates (2)(3)(4).…”

Essential Domain of Receptor Tyrosine Phosphatase β (RPTPβ) for Interaction with Helicobacter pylori Vacuolating Cytotoxin

“…The major action of RPTP␣ is as a positive regulator of Src and Src family kinases through dephosphorylation (48). RPTP␤ promotes cell adhesion, neurite growth, and migration (49). Thus, both RPTP␣ and RPTP␤ have the potential to regulate signal transduction through tightly controlled dephosphorylation of tyrosyl residues in proteins by the binding of specific extracellular ligands or cytoplasmic proteins.…”

“…Thus, both RPTP␣ and RPTP␤ have the potential to regulate signal transduction through tightly controlled dephosphorylation of tyrosyl residues in proteins by the binding of specific extracellular ligands or cytoplasmic proteins. A variety of extracellular ligands of RPTP␤ have been identified; PTN, N-CAM, Ng-CAM, tenascin, contactin, and midkine (49). Among these RPTP␤ ligands, PTN and midkine are secreted proteins that exert their effects through inhibition of RPTP␤ phosphatase activity.…”

“…GRB2, which binds the Tyr-789 (mouse) or Tyr-798 (human) of RPTP␣) (50,51). As the extracellular domain of RPTP␣ is small, it is conceivable that its function may be to tether tyrosine phosphatase activity to the plasma membrane (49). VacA is the first extracellular ligand to be discovered for RPTP␣.…”

Abnormal myelination in the spinal cord of PTPα-knockout mice

“…24 It is also conceivable that a potential compensatory upregulation of other PTPs, such as PTPε that has been identified as a positive modulator of myelination, 25 may be related to abnormal myelination in PTPα KO mice. Taken altogether, our results demonstrate that…”