Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The neuronal protein tyrosine phosphatases encoded by mouse gene Ptprr (PTPBR7, PTP-SL, PTPPBSgamma-42 and PTPPBSgamma-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. Ptprr-/- mice were viable and fertile, and not different from wildtype littermates regarding general physiology or explorative behaviour. Highest PTPRR protein levels are in cerebellum Purkinje cells, but no overt effects of PTPRR deficiency on brain morphology, Purkinje cell number or dendritic branching were detected. However, MAP kinase phosphorylation levels were significantly altered in the PTPRR-deficient cerebellum and cerebrum homogenates. Most notably, increased phospho-ERK1/2 immunostaining density was observed in the basal portion and axon hillock of Ptprr-/- Purkinje cells. Concomitantly, Ptprr-/- mice displayed ataxia characterized by defects in fine motor coordination and balance skills. Collectively, these results establish the PTPRR proteins as physiological regulators of MAP kinase signalling cascades in neuronal tissue and demonstrate their involvement in cerebellum motor function.
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PMID:Altered MAP kinase phosphorylation and impaired motor coordination in PTPRR deficient mice. 1726 27

Hirschsprung disease (HSCR) is a common developmental disorder of the enteric nervous system (ENS). However, the disease mechanisms have not been fully elucidated. To better understand the etiology of HSCR, the role and mechanism of HSCR associated PTPRR (protein tyrosine phosphatase receptor-type R) in the multipotency of ENS progenitors and ENS development were explored. In the present study, the downregulated PTPRR expression in HSCR was reflected by microarray and validated by real-time PCR analyses. Moreover, PTPRR protein was mainly expressed in the cytoplasmic area of primary cultured ENS progenitors (Enteric neural crest cells, ENCCs) and significantly decreased after differentiation induction, which implies the anti-differentiation role in ENCCs. Further study employed an adenovirus transfection system. After genetic modulation, the ENCCs maintained undifferentiated patterns even in GDNF (Glial cell-line derived neurotrophic factor)-mediated directional differentiation, as well as significantly increased EdU positive immunofluorescence in the PTPRR overexpressing group while the development of the ENS was stunted in the PTPRR knockdown fetal gut. Moreover, the expression of ERK1/2 activated by GDNF was significantly decreased as reflected by western-blot or immunofluorescence analyses after genetic modulation in the PTPRR overexpressing group, which suggests the potential mechanism in regulating the MAPK/ERK1/2 pathway. Taken together, These data support the idea that PTPRR may ensure a certain number of neural precursor cells by inhibiting ENCC overt differentiation and maintaining ENCC proliferation, which is considered to be the multipotency of ENCCs, and eventually participate in the development of the ENS, and establish PTPRR protein as negative regulator of MAPK/ERK1/2 signaling cascades in neuronal differentiation and demonstrate their involvement in the pathophysiology of HSCR.
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PMID:Downregulation of Protein Tyrosine Phosphatase Receptor Type R Accounts for the Progression of Hirschsprung Disease. 3102 55