The neuronal protein tyrosine phosphatases encoded by mouse gene Ptprr (PTPBR7, PTP-SL, PTPPBSc-42 and PTPPBSc-37) have been implicated in mitogen-activated protein (MAP) kinase deactivation on the basis of transfection experiments. To determine their physiological role in vivo, we generated mice that lack all PTPRR isoforms. The cerebellum is the major centre of fine motor coordination in the central nervous system, and in addition serves in cognitive processing and sensory discrimination. Abbreviations used: DUSP, dual-specificity phosphatase; ERK, extracellular signal-regulated kinase; KIM, kinase interaction motif; MAPK, mitogen-activated protein kinase; PTP, protein tyrosine phosphatase.

Protein tyrosine phosphatases (PTPs) are central players in many different cellular processes and their aberrant activity is associated with multiple human pathologies. In this review, we present current knowledge on the PTPRR subfamily of classical PTPs that is expressed in neuronal cells and comprises receptor-type (PTPBR7, PTP-SL) as well as cytosolic (PTPPBSγ-37, PTPPBSγ-42) isoforms. The two receptor-type isoforms PTPBR7 and PTP-SL both localize in late endosomes and the Golgi area. PTPBR7, however, is additionally localized at the cell surface and on early endosomes. During cerebellar maturation, PTPBR7 expression in developing Purkinje cells ceases and is replaced by PTP-SL expression in the mature Purkinje cells. All PTPRR isoforms contain a kinase interacting motif that makes them mitogen-activated protein kinase phosphatases. The distinct subcellular localization of the different PTPRR isoforms may reflect differential roles in growth-factor-induced MAPK-mediated retrograde signaling cascades. Studies in PTPRR-deficient mice established that PTPRR isoforms are physiological regulators of MAPK phosphorylation levels. Surprisingly, PTPRR-deficient mice display defects in motor coordination and balancing skills, while cerebellar morphological abnormalities, which are often encountered in ataxic mouse models, are absent. This is reminiscent of the phenotype observed in a handful of mouse mutants that have alterations in cerebellar calcium ion homeostasis. Elucidation of the molecular mechanisms by which PTPRR deficiency imposes impairment of cerebellar neurons and motor coordination may provide candidate molecules for hereditary cerebellar ataxias that still await identification of the corresponding disease genes.Electronic supplementary materialThe online version of this article (doi:10.1007/s12311-008-0088-y) contains supplementary material, which is available to authorized users.

Dimerisation of receptor-type protein tyrosine phosphatases (RPTPs) represents an appealing mechanism to regulate their enzymatic activity. Studies thus far mostly concern the dimerisation behaviour of RPTPs possessing two tandemly oriented catalytic PTP domains. Mouse gene Ptprr encodes four different protein isoforms (i.e. PTPBR7, PTP-SL and PTPPBSgamma-42/37) that contain a single PTP domain. Using selective membrane permeabilisation we here demonstrate that PTP-SL, like PTPBR7, is a single membrane-spanning RPTP. Furthermore, these two receptor-type PTPs constitutively formed homo- and hetero-meric complexes as witnessed in chemical cross-linking and co-immunoprecipitation experiments, in sharp contrast to the cytosolic PTPPBSgamma-42 and PTPPBSgamma-37 PTPRR isoforms. This multimerisation occurs independently of the PTP domain and requires the transmembrane domain and/or the proximal hydrophobic region. Using overexpression of a PTPBR7 mutant that essentially lacks the intracellular PTP domain-containing segment, a monomer-mimicking state was forced upon full-length PTPBR7 immunoprecipitates. This resulted in a significant increase in the enzymatic activity of the PTPRR PTP domain, which strengthens the notion that multimerisation represents a general mechanism to tone down RPTP catalytic activity.

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Background: Spatio-temporal control of extracellular signal-regulated kinase (ERK) activity, a critical determinant of the cell's response to growth factors, requires timely dephosphorylation of its regulatory tyrosine and/or threonine residue by MAPK phosphatases. We studied the physiological role of kinase interaction motif (KIM)-containing protein tyrosine phosphatases (PTPs) in the control of EGF-and NGF-induced ERK activity in neuroendocrine PC12 cells.