Phosphorylation of WAVE1 regulates actin polymerization and dendritic spine morphology

Genetic ablation of WRC components affects spine morphology and excitability.

“Rearrangements of the actin cytoskeleton strongly influence the formation, retraction, motility, stability, and shape of the dendritic spines (Tada and Sheng, 2006), and genetic ablation of WRC components affects spine morphology and excitability (Grove et al., 2004, Kim et al., 2006, Soderling et al., 2007, Wiens et al., 2005).”

The observed spine dysmorphogenesis is in line with defects in WRC components, loss of FMRP, overexpression of ARC, or Rac1 blockade during early development.

“the observed spine dysmorphogenesis is in line with defects in the WRC components (Grove et al., 2004, Kim et al., 2006, Soderling et al., 2007), loss of FMRP (Comery et al., 1997, Cruz-Martín et al., 2010, Galvez and Greenough, 2005, Irwin et al., 2002), overexpression of ARC (Peebles et al., 2010), or Rac1 blockade during early development (Tashiro and Yuste, 2004).”

Phosphorylation of WAVE or ABI mediates the activation or inhibition of the WAVE complex, depending on specific phosphorylation sites.

“The phosphorylation of WAVE or ABI mediates the activation or inhibition of the WAVE complex, depending on specific phosphorylation sites22,36 (Figs. 2 and 3).”

Ser310 is the major phosphorylation site, and a Ser310Ala mutation blocks the inhibitory effect of CDK5 phosphorylation on WAVE1-mediated actin polymerization in vitro.

“Ser310 is the major phosphorylation site, and a Ser310Ala mutation blocks the inhibitory effect of CDK5 phosphorylation on WAVE1-mediated actin polymerization in vitro22.”

CDK5 phosphorylation of the native WAVE1 complex purified from the rat brain or recombinant WAVE1 inhibits ARP2/3-mediated actin polymerization in vitro.

“CDK5 phosphorylation of the native WAVE1 complex purified from the rat brain or recombinant WAVE1 inhibits ARP2/3-mediated actin polymerization in vitro22.”

The WAVE1 complex was identified from brain lysates as an interactor of CDK5 complexed with p35, an activating subunit of CDK5.

“The WAVE1 complex was identified from brain lysates as an interactor of CDK5 complexed with p35, an activating subunit of CDK522.”

Compared with their paralogs, WAVE1, CYFIP2, NCKAP1 and ABI2 are relatively abundant in the brain.

“Compared with their paralogs, WAVE1, CYFIP2, NCKAP1 and ABI2 are relatively abundant in the brain19,20,22 (Fig. 1).”

CDK5 phosphorylates WAVE1 at Ser310, Ser397 and Ser441 with high basal stoichiometry in the intact brain, brain slices or cultured neurons.

“Notably, CDK5 phosphorylates WAVE1 at Ser310, Ser397 and Ser441 with high basal stoichiometry in the intact brain, brain slices or cultured neurons22.”

CDK5 phosphorylates Ser310, Ser397 and Ser441 within the proline-rich region of WAVE1, but these three sites are not phosphorylated by ERK.

“CDK5 phosphorylates Ser310, Ser397 and Ser441 within the proline-rich region of WAVE1, but these three sites are not phosphorylated by ERK.”

WAVE1 deletion decreases the density and alters the morphology of dendritic spines.

“WAVE1 deletion decreases the density and alters the morphology of dendritic spines22,61.”

The WAVE1 complex is localized to dendritic spines and plays an important role in the regulation of dendritic spine morphology.

“The WAVE1 complex is localized to dendritic spines and plays an important role in the regulation of dendritic spine morphology.”

Experimentally decreasing WAVE1 expression causes a decrease in the density of mature dendritic spines with a larger head and shorter neck but increases the density of filopodial dendritic protrusions.

“Experimentally decreasing WAVE1 expression causes a decrease in the density of mature dendritic spines with a larger head and shorter neck but increases the density of filopodial dendritic protrusions22.”

CK2 phosphorylation of the WCA domain of WAVEs and/or CDK5 phosphorylation of the proline-rich region of WAVE1 may confer an inhibitory state, whereas protein phosphatase-mediated dephosphorylation of these sites may activate the WAVE complex.

“Thus, CK2 phosphorylation of the WCA domain of WAVEs and/or CDK5 phosphorylation of the proline-rich region of WAVE1 may confer an inhibitory state, whereas protein phosphatase-mediated dephosphorylation of these sites may activate the WAVE complex22,43,44,48,49.”

Several studies have used intact WAVE complexes isolated from the brain or cells.

“In fact, several studies have used intact WAVE complexes isolated from the brain or cells19,20,22,179.”

WAVE1 exhibits high levels of basal phosphorylation in neurons or the brain, but this baseline phosphorylation is not present in the purified recombinant WAVE complex.

“Although WAVE1 exhibits high levels of basal phosphorylation in neurons or the brain22,49, this baseline phosphorylation is not present in the purified recombinant WAVE complex.”