title: Proline-rich tyrosine kinase 2 regulates hippocampal long-term depression.
abstract: Proline-rich tyrosine kinase 2 (PYK2), also known as cell adhesion kinase beta or protein tyrosine kinase 2b, is a calcium-dependent signaling protein involved in cell migration. Phosphorylation of residue Y402 is associated with activation of PYK2 and leads to the recruitment of downstream signaling molecules. PYK2 was previously implicated in long-term potentiation (LTP); however, the role of PYK2 in long-term depression (LTD) is unknown. Here, we report that PYK2 is activated by NMDA receptor stimulation (chemical LTD) in cultured neurons. Small hairpin RNA-mediated knockdown of PYK2 blocks LTD, but not LTP, in hippocampal slice cultures. We find that the Y402 residue and, to a lesser extent, PYK2 kinase activity contribute to PYK2's role in LTD. Knockdown experiments indicate that PYK2 is required to suppress NMDA-induced extracellular signal-regulated kinase (ERK) phosphorylation. Overexpression of PYK2 depresses NMDA-induced ERK phosphorylation and inhibits LTP, but not LTD. Our data indicate that PYK2 is critical for the induction of LTD, possibly in part by antagonizing ERK signaling in hippocampal neurons.
authors.affiliation: Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Honor
authors.initials: H
authors.lastname: Hsin
authors.forename: Myung Jong
authors.initials: MJ
authors.lastname: Kim
authors.forename: Chi-Fong
authors.initials: CF
authors.lastname: Wang
authors.forename: Morgan
authors.initials: M
authors.lastname: Sheng
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001703:Biophysics / Q000379:methods; D002461:Cell Line, Transformed; D004558:Electric Stimulation / Q000379:methods; D051418:Focal Adhesion Kinase 2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000235:genetics; D006624:Hippocampus / Q000502:physiology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D036881:Long-Term Synaptic Depression / Q000235:genetics / Q000502:physiology*; D008239:Lysine / Q000235:genetics / Q000378:metabolism; D009924:Organ Culture Techniques; D010766:Phosphorylation; D034622:RNA Interference / Q000502:physiology; D051381:Rats; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D012694:Serine / Q000235:genetics / Q000378:metabolism; D016559:Tacrolimus / Q000494:pharmacology; D014162:Transfection / Q000379:methods
chemical_list: D051418:Focal Adhesion Kinase 2; D049452:Green Fluorescent Proteins; D007166:Immunosuppressive Agents; D008239:Lysine; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D012694:Serine; D016559:Tacrolimus
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