Phosphorylation of WAVE1 regulates actin polymerization and dendritic spine morphology.
WAVE1--the Wiskott-Aldrich syndrome protein (WASP)--family verprolin homologous protein 1--is a key regulator of actin-dependent morphological processes in mammals, through its ability to activate the actin-related protein (Arp2/3) complex. Here we show that WAVE1 is phosphorylated at multiple sites by cyclin-dependent kinase 5 (Cdk5) both in vitro and in intact mouse neurons. Phosphorylation of WAVE1 by Cdk5 inhibits its ability to regulate Arp2/3 complex-dependent actin polymerization. Loss of WAVE1 function in vivo or in cultured neurons results in a decrease in mature dendritic spines. Expression of a dephosphorylation-mimic mutant of WAVE1 reverses this loss of WAVE1 function in spine morphology, but expression of a phosphorylation-mimic mutant does not. Cyclic AMP (cAMP) signalling reduces phosphorylation of the Cdk5 sites in WAVE1, and increases spine density in a WAVE1-dependent manner. Our data suggest that phosphorylation/dephosphorylation of WAVE1 in neurons has an important role in the formation of the filamentous actin cytoskeleton, and thus in the regulation of dendritic spine morphology.
Kim
Yong
Y
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, 1230 York Avenue, New York, New York 10021, USA.
Sung
Jee Young
JY
Ceglia
Ilaria
I
Lee
Ko-Woon
KW
Ahn
Jung-Hyuck
JH
Halford
Jonathan M
JM
Kim
Amie M
AM
Kwak
Seung P
SP
Park
Jong Bae
JB
Ho Ryu
Sung
S
Schenck
Annette
A
Bardoni
Barbara
B
Scott
John D
JD
Nairn
Angus C
AC
Greengard
Paul
P
D000199:Actins / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001704:Biopolymers / Q000378:metabolism; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism; D003599:Cytoskeleton / Q000737:chemistry / Q000378:metabolism*; D003712:Dendrites / Q000378:metabolism / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D011817:Rabbits; D051300:Wiskott-Aldrich Syndrome Protein Family / Q000378:metabolism*
D000199:Actins; D001704:Biopolymers; D051300:Wiskott-Aldrich Syndrome Protein Family; D000242:Cyclic AMP; D051360:Cyclin-Dependent Kinase 5