Proline-rich tyrosine kinase 2 regulates hippocampal long-term depression.
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.
Hsin
Honor
H
Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Kim
Myung Jong
MJ
Wang
Chi-Fong
CF
Sheng
Morgan
M
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
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
Proc Natl Acad Sci U S A. 2003 Sep 16;100(19):10740-5
12960403
J Neurosci. 2000 Sep 1;20(17):6478-87
10964954
Science. 1989 Aug 25;245(4920):862-6
2549638
Genes Dev. 2005 Sep 1;19(17):2000-15
16107614
Science. 1992 Jul 10;257(5067):206-11
1321493
Neurobiol Aging. 2007 Feb;28(2):226-37
16448724
J Cell Biol. 2007 Sep 10;178(6):1053-64
17846174
J Biol Chem. 2003 Mar 28;278(13):11502-12
12514172
J Neurosci. 2008 Aug 13;28(33):8178-88
18701680
Proc Natl Acad Sci U S A. 2003 Jul 22;100(15):8987-92
12851457
J Neurosci. 2004 Jan 28;24(4):916-27
14749436
Nature. 1996 Oct 10;383(6600):547-50
8849729
Neuron. 1998 Nov;21(5):1151-62
9856470
Nat Rev Neurosci. 2004 Mar;5(3):173-83
14976517
J Cell Sci. 2007 Sep 1;120(Pt 17):3034-44
17684059
Nat Cell Biol. 2006 Mar;8(3):227-37
16474385
Neuron. 2008 Jan 24;57(2):248-62
18215622
J Biol Chem. 2008 Dec 5;283(49):34101-7
18815127
J Neurosci. 2002 Mar 15;22(6):2054-62
11896145
Cell. 2001 Nov 30;107(5):617-29
11733061
J Biol Chem. 1997 Aug 1;272(31):19103-6
9235897
Science. 2002 Feb 1;295(5556):868-72
11786607
Annu Rev Neurosci. 2007;30:79-97
17280523
J Neurosci. 2003 Jul 2;23(13):5503-6
12843250
J Cereb Blood Flow Metab. 2000 Mar;20(3):505-12
10724115
Cell. 2002 Aug 23;110(4):443-55
12202034
J Cell Sci. 2000 Sep;113 ( Pt 17):3063-72
10934044
Learn Mem. 1999 Sep-Oct;6(5):478-90
10541468
J Biol Chem. 2004 Aug 6;279(32):33315-22
15166227
Nature. 1995 Aug 31;376(6543):737-45
7544443
Nature. 1994 Jun 9;369(6480):486-8
7515479
Trends Neurosci. 1999 Jun;22(6):257-63
10354603
J Neurosci. 2008 Jun 25;28(26):6583-91
18579731
J Neurosci. 1999 May 1;19(9):3535-44
10212313
Science. 1993 Aug 20;261(5124):1051-5
8394601
Neuron. 2005 Jun 16;46(6):905-16
15953419
Annu Rev Biochem. 2007;76:823-47
17243894
Neuron. 2007 Nov 8;56(3):488-502
17988632
J Cell Biol. 2008 Jan 14;180(1):187-203
18195107
Nat Neurosci. 1998 Nov;1(7):602-9
10196568
Cell. 1995 Jan 27;80(2):179-85
7834738
Neuron. 2005 Jun 2;46(5):745-60
15924861
Neuron. 2004 Dec 2;44(5):749-57
15572107
J Neurosci. 2000 Jul 15;20(14):5329-38
10884317
J Neurosci. 2010 Jan 13;30(2):449-63
20071509
J Neurosci. 2003 Jul 16;23(15):6327-37
12867517
EMBO Rep. 2006 Nov;7(11):1117-23
17039254
J Biol Chem. 2003 Apr 25;278(17):15040-8
12576483
Neuron. 2001 Dec 20;32(6):1133-48
11754843
Curr Biol. 2007 Oct 23;17(20):1752-8
17935993
J Cell Biol. 1997 Oct 20;139(2):529-39
9334354
Nat Neurosci. 2004 Oct;7(10):1104-12
15361876
Biochem J. 2008 Mar 15;410(3):513-23
18031286
J Neurochem. 2006 Apr;97 Suppl 1:16-23
16635246
Neuron. 2001 Feb;29(2):485-96
11239437
Curr Opin Neurobiol. 2006 Feb;16(1):95-101
16361095
Nature. 1989 Aug 17;340(6234):554-7
2549423
Science. 1998 Feb 27;279(5355):1363-7
9478899
Science. 2002 Apr 19;296(5567):550-3
11910072
Science. 1992 Dec 18;258(5090):1903-10
1361685
Nature. 1998 Dec 3;396(6710):433-9
9853749
J Biol Chem. 1999 Mar 26;274(13):8917-24
10085136
J Biol Chem. 2004 Mar 26;279(13):12009-19
14701796