Phosphorylation of the Actin Binding Protein Drebrin at S647 Is Regulated by Neuronal Activity and PTEN

Abstract

Defects in actin dynamics affect activity-dependent modulation of synaptic transmission and neuronal plasticity, and can cause cognitive impairment. A salient candidate actin-binding protein linking synaptic dysfunction to cognitive deficits is Drebrin (DBN). However, the specific mode of how DBN is regulated at the central synapse is largely unknown. In this study we identify and characterize the interaction of the PTEN tumor suppressor with DBN. Our results demonstrate that PTEN binds DBN and that this interaction results in the dephosphorylation of a site present in the DBN C-terminus - serine 647. PTEN and pS647-DBN segregate into distinct and complimentary compartments in neurons, supporting the idea that PTEN negatively regulates DBN phosphorylation at this site. We further demonstrate that neuronal activity increases phosphorylation of DBN at S647 in hippocampal neurons in vitro and in ex vivo hippocampus slices exhibiting seizure activity, potentially by inducing rapid dissociation of the PTEN:DBN complex. Our results identify a novel mechanism by which PTEN is required to maintain DBN phosphorylation at dynamic range and signifies an unusual regulation of an actin-binding protein linked to cognitive decline and degenerative conditions at the CNS synapse.

Drebrin coordinates the actin and microtubule cytoskeleton during the initiation of axon collateral branches

“…Phosphatase and tensin homolog (PTEN) is generally considered to be a lipid phosphosphatase that antagonizes the activation of the Akt-mTOR pathway by phosphoinositide 3-kinase activity (van Diepen and Eickholt, 2008; Kreis et al, 2014). However, PTEN also has phosphatase activity toward some proteins and PTEN mediates the dephosphorylation of S647 in the C domain of drebrin (Kreis et al, 2013). Although the full spectrum of the role of S647 phosphorylation is not well understood, it is considered to positively regulate drebrin functions.…”

Cytoskeletal social networking in the growth cone: How +TIPs mediate microtubule‐actin cross‐linking to drive axon outgrowth and guidance

“…One recent study disputed this, indicating that a loss of Drebrin-binding caused only minimal effects [Dun et al, 2012]; but others have illustrated that a loss of this interaction could affect axon extension and actin-microtubule coupling in the growth cone [Geraldo et al, 2008;Worth et al, 2013;Tanabe et al, 2014;Sonego et al, 2015]. These studies indicated that Drebrin is regulated downstream of Cdk5 and potentially PTEN phosphorylation [Kreis et al, 2013;Worth et al, 2013;Tanabe et al, 2014;Sonego et al, 2015]. Cdk5 was shown to phosphorylate Drebin on Ser142, causing an open conformation that allowed both binding to actin filaments and EB3microtubule interactions.…”

Drebrin and Spermatogenesis

“…Studies in recent years have shown that cyclin-dependent kinase 5 (Cdk5)-p35, a Ser/Thr protein kinase, can phosphorylate drebrin to modulate neuronal migration (Tanabe et al 2014). Phosphatase and tensin homolog (PTEN), a known binding partner of drebrin (Table 17.1), was also shown to dephosphorylate drebrin at Ser-647 in the brain to regulate neuronal activity (Kreis et al 2013). It will be of interest to determine if these proteins or other testis-specific kinases and phosphatases would play a role in modulating the function of drebrin.…”

“…Cdk5 is the kinase known to phosphorylate drebrin at Ser-142 (Worth et al 2013). PTEN is known to dephosphorylate Ser-647 in drebrin A (Kreis et al 2013), which corresponds to Ser-601 in drebrin E based on sequence homology alignment analysis…”