JNK1 phosphorylation of SCG10 determines microtubule dynamics and axodendritic length

Abstract

c-Jun NH2-terminal kinases (JNKs) are essential during brain development, when they regulate morphogenic changes involving cell movement and migration. In the adult, JNK determines neuronal cytoarchitecture. To help uncover the molecular effectors for JNKs in these events, we affinity purified JNK-interacting proteins from brain. This revealed that the stathmin family microtubule-destabilizing proteins SCG10, SCLIP, RB3, and RB3′ interact tightly with JNK. Furthermore, SCG10 is also phosphorylated by JNK in vivo on sites that regulate its microtubule depolymerizing activity, serines 62 and 73. SCG10-S73 phosphorylation is significantly decreased in JNK1−/− cortex, indicating that JNK1 phosphorylates SCG10 in developing forebrain. JNK phosphorylation of SCG10 determines axodendritic length in cerebrocortical cultures, and JNK site–phosphorylated SCG10 colocalizes with active JNK in embryonic brain regions undergoing neurite elongation and migration. We demonstrate that inhibition of cytoplasmic JNK and expression of SCG10-62A/73A both inhibited fluorescent tubulin recovery after photobleaching. These data suggest that JNK1 is responsible for regulation of SCG10 depolymerizing activity and neurite elongation during brain development.

SCLIP Is Crucial for the Formation and Development of the Purkinje Cell Dendritic Arbor

“…For instance, SCLIP might differently regulate microtubules and their dynamics depending on its phosphorylation state in different neurons or in axonal and dendritic compartments. Phosphorylation has been shown to tightly control the interaction of stathmin family proteins with tubulin (Curmi et al, 1997;Steinmetz et al, 2001;Amayed et al, 2002;Honnappa et al, 2006) and seems necessary to mediate the regulatory functions of stathmin and SCG10 in axonal development (Tararuk et al, 2006;Watabe-Uchida et al, 2006). Alternatively, SCLIP might interact with specific axonal or dendritic partners mediating its functions.…”

Initiating and Growing an Axon

“…Numerous lines of evidence suggest this pathway is also important for axonal extension (Leppa et al 1998;Rosso et al 2005;Xiao et al 2006;Ciani and Salinas 2007;Eminel et al 2008). JNKs show constitutively high activity within neurons and phosphorylate various cytoskeletal proteins involved in axon extension, including MAP1B, MAP2, tau, and SCG10, among others (Kyriakis and Avruch 1990;Otto et al 2000;Neidhart et al 2001;Tararuk et al 2006;Yamauchi et al 2006;Ciani and Salinas 2007). Axonal transport is modulated by JNK, and it has been proposed that JNK triggers the release of cargoes, such as tubulin, from kinesin complexes (Stagi et al 2006;Horiuchi et al 2007).…”

JNK regulates FoxO-dependent autophagy in neurons

“…This action of JNK is important for neurite formation. Thus, JNK contributes to bone morphogenic proteinstimulated dendrite formation (Podkowa et al 2010), the structure of dendritic architecture (Coffey et al 2000;Bjorkblom et al 2005), axodendritic length (Tararuk et al 2006), and axonal regeneration (Barnat et al 2010). Moreover, JNK can regulate kinesin-mediated fast axonal transport on microtubules (Morfini et al 2006(Morfini et al , 2009) and contributes to the regulation of synaptic plasticity (Chen et al 2005;Zhu et al 2005;Li et al 2007; Thomas et al 2008).…”

“…JNK-induced phosphorylation of microtubule-associated proteinsincluding Doublecortin (Gdalyahu et al 2004), MAP1B (Chang et al 2003;Barnat et al 2010), MAP2 (Chang et al 2003), the stathmin protein family of microtubuledestabilizing proteins (Tararuk et al 2006), and Tau (Yoshida et al 2004)-may influence microtubule function. This action of JNK is important for neurite formation.…”