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The protein tyrosine phosphatases (PTPs) have emerged as critical players in diverse cellular functions. The focus of this review is the leukocyte common antigen-related (LAR) subfamily of receptor PTPs (RPTPs). This subfamily is composed of three vertebrate homologs, LAR, RPTP-sigma, and RPTP-delta, as well as few invertebrates orthologs such as Dlar. LAR-RPTPs have a predominant function in nervous system development that is conserved throughout evolution. Proteolytic cleavage of LAR-RPTP proproteins results in the noncovalent association of an extracellular domain resembling cell adhesion molecules and intracellular tandem PTPs domains, which is likely regulated via dimerization. Their receptor-like structures allow them to sense the extracellular environment and transduce signals intracellularly via their cytosolic PTP domains. Although many interacting partners of the LAR-RPTPs have been identified and suggest a role for the LAR-RPTPs in actin remodeling, very little is known about the mechanisms of action of RPTPs. LAR-RPTPs recently raised a lot of interest when they were shown to regulate neurite growth and nerve regeneration in transgenic animal models. In addition, LAR-RPTPs have also been implicated in metabolic regulation and cancer. This RPTP subfamily is likely to become important as drug targets in these various human pathologies, but further understanding of their complex signal transduction cascades will be required.

Receptor protein tyrosine phosphatase sigma (RPTPsigma) plays a role in inhibiting axon growth during development. It has also been shown to slow axon regeneration after peripheral nerve injury and inhibit axon regeneration in the optic nerve. Here, we assessed the ability of the corticospinal tract (CST) axons to regenerate after spinal hemisection and contusion injury in RPTPsigma deficient (RPTPsigma(-/-)) mice. We show that damaged CST fibers in RPTPsigma(-/-) mice regenerate and appear to extend for long distances after a dorsal hemisection or contusion injury of the thoracic spinal cord. In contrast, no long distance axon regeneration of CST fibers is seen after similar lesions in wild-type mice. In vitro experiments indicate that cerebellar granule neurons from RPTPsigma(-/-) mice have reduced sensitivity to the inhibitory effects of chondroitin sulfate proteoglycan (CSPG) substrate, but not myelin, which may contribute to the growth of CST axons across the CSPG-rich glial scar. Our data suggest that RPTPsigma may function to prevent axonal growth after injury in the adult mammalian spinal cord and could be a target for promoting long distance regeneration after spinal cord injury.

The leukocyte common antigen-related (LAR) subfamily of receptor protein tyrosine phosphatases (RPTPs), LAR, RPTP-, and RPTP-␦, regulate neuroendocrine development, axonal regeneration, and hippocampal long-term potentiation in mammals. In Drosophila, RPTPs are required for appropriate axon targeting during embryonic development. In contrast, deletion of any one of the three LAR-RPTP family members in mammals does not result in gross axon targeting defects. Both RPTP-and RPTP-␦ are highly expressed in the developing mammalian nervous system, suggesting they might be functionally redundant. To test this hypothesis, we generated RPTPand RPTP-␦ (RPTP-/␦) double-mutant mice. Although embryonic day 18.5 RPTP-and RPTP-␦ single-mutant embryos were viable, RPTP-/␦ double mutants were paralyzed, were never observed to draw a breath, and died shortly after cesarean section. RPTP-/␦ double mutants exhibit severe muscle dysgenesis and severe loss of motoneurons in the spinal cord. Detailed analysis of the projections of phrenic nerves in RPTP-/␦ double mutants indicated that these motoneuron axons emerge normally from the cervical spinal cord, but stall on reaching the diaphragm. Our results demonstrate that RPTP-and RPTP-␦ complement each other functionally during mammalian development, and reveal an essential contribution of RPTP-and RPTP-␦ to appropriate motoneuron axon targeting during mammalian axonogenesis.

Congenital anomalies affecting the ureter-bladder junction are frequent in newborns and are often associated with other developmental defects. However, the molecular and morphological processes underlying these malformations are still poorly defined. In this study, we identified the leukocyte antigen-related (LAR) family protein tyrosine phosphatase, receptor type, S and F (Ptprs and Ptprf [also known as Lar], respectively), as crucially important for distal ureter maturation and craniofacial morphogenesis in the mouse. Embryos lacking both Ptprs and Ptprf displayed severe urogenital malformations, characterized by hydroureter and ureterocele, and craniofacial defects such as cleft palate, micrognathia, and exencephaly. The detailed analysis of distal ureter maturation, the process by which the ureter is displaced toward its final position in the bladder wall, leads us to propose a revised model of ureter maturation in normal embryos. This process was deficient in embryos lacking Ptprs and Ptprf as a result of a marked reduction in intrinsic programmed cell death, thereby causing urogenital system malformations. In cell culture, Ptprs bound and negatively regulated the phosphorylation and signaling of the Ret receptor tyrosine kinase, whereas Ptprs-induced apoptosis was inhibited by Ret expression. Together, these results suggest that ureter positioning is controlled by the opposing actions of Ret and LAR family phosphatases regulating apoptosis-mediated tissue morphogenesis.

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Background: PTP-PEST regulates cell migration as part of many protein complexes. Results: SKAP-Hom is a substrate of PTP-PEST that is required for proper fibroblasts migration. Enhanced migration was observed when SKAP-Hom-deficient fibroblasts are rescued with its SH3 domain mutant. Conclusion: As a novel substrate of PTP-PEST, SKAP-Hom is important in cellular migration. Significance: PTP-PEST regulates migration through a new complex involving SKAP-Hom.

Several protein tyrosine phosphatases (PTPs) expressed in insulin sensitive-tissues are proposed to attenuate insulin action and could act as key regulators of the insulin receptor (IR) signaling pathway. Among these PTPs, RPTPsigma is expressed in relatively high levels in insulin-target tissues. We show that RPTPsigma-/- knockout mice have reduced plasma glucose and insulin concentrations in the fasted state compared with their wild-type siblings. The knockout animals were also more sensitive to exogenous insulin as assayed by insulin-tolerance tests. Despite increased whole-body insulin sensitivity, tyrosine phosphorylation of the IR was not increased in muscle of RPTPsigma-/- animals, as would be expected in insulin-sensitive animals. Instead, the levels of IR tyrosine phosphorylation and PI3-kinase activity were reduced in the muscle of knockout animals stimulated with insulin in vivo. However, insulin-stimulated Akt serine phosphorylation was essentially identical between both groups of mice. Accordingly, muscles isolated from RPTPsigma-/- mice did not have a significant increase in glucose uptake in response to insulin, suggesting that RPTPsigma did not play a direct role in this process. Taken together, our results suggest an indirect modulation of the IR signaling pathways by RPTPsigma. Since low dose injection of growth hormone (GH) normalized the response to exogenous insulin in RPTPsigma-/- mice, we propose that the insulin hypersensitivity observed in RPTPsigma-/- mice is secondary to their neuroendocrine dysplasia and GH/IGF-1 deficiency.