A δ-Catenin Signaling Pathway Leading to Dendritic Protrusions

Abstract

␦-Catenin is a synaptic adherens junction protein pivotally positioned to serve as a signaling sensor and integrator. Expression of ␦-catenin induces filopodia-like protrusions in neurons. Here we show that the small GTPases of the Rho family act coordinately as downstream effectors of ␦-catenin. A dominant negative Rac prevented ␦-catenin-induced protrusions, and Cdc42 activity was dramatically increased by ␦-catenin expression. A kinase dead LIMK (LIM kinase) and a mutant Cofilin also prevented ␦-catenin-induced protrusions. To link the effects of ␦-catenin to a physiological pathway, we noted that (S)-3,5-dihydroxyphenylglycine (DHPG) activation of metabotropic glutamate receptors induced dendritic protrusions that are very similar to those induced by ␦-catenin. Furthermore, ␦-catenin RNA-mediated interference can block the induction of dendritic protrusions by DHPG. Interestingly, DHPG dissociated PSD-95 and N-cadherin from the ␦-catenin complex, increased the association of ␦-catenin with Cortactin, and induced the phosphorylation of ␦-catenin within the sites that bind to these protein partners.␦-Catenin is a component of the synaptic adherens junction that is necessary for normal learning and memory (1). In the absence of ␦-catenin, mice have severe deficits in several types of memory as well as synaptic plasticity. However, the functional basis for these deficits is not obvious, particularly because the morphological changes in ␦-catenin null mice are minimal. ␦-Catenin contains 10 Armadillo repeats (a 42-amino acid motif, originally described in the Drosophila segment polarity gene, armadillo) spaced in the characteristic arrangement of all members of this gene family which includes the prototypical member, p120 ctn , as well as p0071, ARVCF (Armadillo Repeat gene deleted in Velo-Cardio-Facial syndrome) (2), and the plakophilins, both components of the desmosome (3-6). The core functions of this protein family are stabilization of cadherins by binding to a highly conserved sequence in the juxtamembrane region and regulatory coordination over Rho GTPases (7). ␦-Catenin is localized to the post-synaptic adherens junction, collaborates with Rho GTPases to set a balance between neurite elongation and branching, and robustly induces dendritic protrusions (8). Among the cadherin binding family members, ␦-catenin is the only one that is a neural-specific protein. However, ␦-catenin null mice develop normally, whereas p120 ctn can regulate synapse and spine development (9).Because both p120 ctn and ␦-catenin are expressed in neurons, an important question is the added functionality provided by co-expression of these paralogs. ⌱n contrast to p120 ctn , ␦-catenin contains a short carboxyl-terminal motif that corresponds to a ligand sequence for PDZ (postsynaptic density-95 (PSD-95) 6 /discs large/zona occludens-1) domain-containing proteins. Through the versatility of this domain, the multiple complex interactions of ␦-catenin with the synapse arise. ␦-Catenin binds to the synaptic scaffolding molecule (S-SCAM) (...

Cadherins and catenins in dendrite and synapse morphogenesis

“…One study indicated that overexpression of d-catenin leads to filopodia like protrusions in a manner consistent with functional cooperation of d-catenin with the small GTP binding proteins of the Rho family, 45 while knockdown of d-catenin leads to a decrease in mature spines and increase in filopodia. In contrast, another study indicated that loss of d-catenin the d-catenin N-term mouse model or knockdown in cultured primary neurons leads to an increase in spine and synapse density and function during development.…”

“…42 The small GTP binding proteins, Rac and Rho have well defined critical roles in dendrite outgrowth and branching. 43 Interestingly, while both p120ctn 44 and d-catenin 45 influence the levels of active Rac and increases the levels of active Rho, 39 a d-catenin mouse model does not have any alterations in the global levels of Rac and Rho.…”

Xenopus δ-catenin is essential in early embryogenesis and is functionally linked to cadherins and small GTPases

“…In common with other p120 subfamily members, such effects are believed to occur mainly through the direct or indirect association of -catenin with small GTPases (RhoA and Rac1), and consequent downstream effectors (Abu-Elneel et al, 2008;Kim et al, 2008a;Kim et al, 2008b;Martinez et al, 2003). Finally, -catenin co-precipitates with Kaiso (Rodova et al, 2004), a POZ zinc-finger transcription factor that acts in various ways at gene promoters (Daniel, 2007;Ioka et al, 2009;Ruzov et al, 2009a;Ruzov et al, 2009b;van Roy and McCrea, 2005).…”

Upregulation of δ‐catenin is associated with poor prognosis and enhances transcriptional activity through Kaiso in non‐small‐cell lung cancer

“…(18)(19)(20) Latterly, the critical role of d-catenin in the modulation of cellular morphogenesis was found. (21)(22)(23)(24) Similar to p120ctn, d-catenin could bind to the junxtamembrane domain (JMD) of E-cadherin (16,25) and regulate cadherin-cytoskeletal connections indirectly through functional interactions with Rho GTPases. (26) It has become clear that d-catenin is expressed in a variety of cancer tissues, including prostate, breast and esophageal tumors.…”