Reduced NMDA receptor tyrosine phosphorylation in PTPalpha-deficient mouse synaptosomes is accompanied by inhibition of four src family kinases and Pyk2: an upstream role for PTPalpha in NMDA receptor regulation.
Mice lacking protein tyrosine phosphatase alpha (PTPalpha) exhibited defects in NMDA receptor (NMDAR)-associated processes such as learning and memory, hippocampal neuron migration, and CA1 hippocampal long-term potentiation (LTP). In vivo molecular effectors linking PTPalpha and the NMDAR have not been reported. Thus the involvement of PTPalpha as an upstream regulator of NMDAR tyrosine phosphorylation was investigated in synaptosomes of wild-type and PTPalpha-null mice. Tyrosine phosphorylation of the NMDAR NR2A and NR2B subunits was reduced upon PTPalpha ablation, indicating a positive effect of this phosphatase on NMDAR phosphorylation via intermediate molecules. The NMDAR is a substrate of src family tyrosine kinases, and reduced activity of src, fyn, yes and lck, but not lyn, was apparent in the absence of PTPalpha. In addition, autophosphorylation of proline-rich tyrosine kinase 2 (Pyk2), a tyrosine kinase linked to NMDAR signaling, was also reduced in PTPalpha-deficient synaptosomes. Altered protein tyrosine phosphorylation was not accompanied by altered expression of the NMDAR or the above tyrosine kinases at any stage of PTPalpha-null mouse development examined. In a human embryonic kidney (HEK) 293 cell expression system, PTPalpha enhanced fyn-mediated NR2A and NR2B tyrosine phosphorylation by several-fold. Together, these findings provide evidence that aberrant NMDAR-associated functions in PTPalpha-null mice are due to impaired NMDAR tyrosine phosphorylation resulting from the reduced activity of probably more than one of the src family kinases src, fyn, yes and lck. Defective NMDAR activity in these mice may also be linked to the loss of PTPalpha as an upstream regulator of Pyk2.
Le
Hoa T
HT
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
Maksumova
Lola
L
Wang
Jing
J
Pallen
Catherine J
CJ
D000818:Animals; D002460:Cell Line; D051418:Focal Adhesion Kinase 2 / Q000037:antagonists & inhibitors*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000172:deficiency* / Q000502:physiology*; D051076:Proto-Oncogene Proteins c-fyn / Q000378:metabolism; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4; D011956:Receptors, Cell Surface / Q000172:deficiency* / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013574:Synaptosomes / Q000201:enzymology / Q000378:metabolism*; D014018:Tissue Distribution; D014443:Tyrosine / Q000378:metabolism*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
C120997:NR2A NMDA receptor; C121001:NR2B NMDA receptor; D011956:Receptors, Cell Surface; D016194:Receptors, N-Methyl-D-Aspartate; D014443:Tyrosine; D051418:Focal Adhesion Kinase 2; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn; C496053:Ptk2b protein, mouse; D019061:src-Family Kinases; C516841:PTPRA protein, human; D017027:Protein Tyrosine Phosphatases; C516843:Ptpra protein, mouse; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4