Protein Kinase C Phosphorylation of a γ-Protocadherin C-terminal Lipid Binding Domain Regulates Focal Adhesion Kinase Inhibition and Dendrite Arborization

Abstract

Background: ␥-Protocadherin adhesion molecules regulate dendrite arborization by inhibiting focal adhesion kinase (FAK). Results: Protein kinase C (PKC) phosphorylation of a C-terminal serine disrupts ␥-protocadherin inhibition of FAK and reduces dendrite arborization. Conclusion:The ability of the ␥-protocadherins to promote dendrite arborization is regulated by phosphorylation. Significance: These data provide much-needed mechanistic insight into the regulation of a critical neurodevelopmental adhesion molecule.

γ-Protocadherins Interact with Neuroligin-1 and Negatively Regulate Dendritic Spine Morphogenesis

“…In any case, our in vivo KO results are strongly supported by the demonstration that that overexpression of γ-Pcdhs in vivo has the opposite effect on cortical spine density as does KO, and that γ-Pcdhs can suppress the potentiation of spine density by Nlg1 overexpression in hippocampal neurons. We suggest that γ-Pcdh function may be differentially regulated by distinct cis -interaction partners, either through their extracellular domains as observed here for Nlg1 or through intracellular signaling partners of their cytoplasmic domains, and that these may vary across neuronal subsets or developmental stages (Keeler et al, 2015a; Mah and Weiner, 2016; Mah et al, 2016). …”

“…In the mammalian forebrain, the γ-Pcdhs are critical for proper dendritic arbor complexity, both in vivo and in vitro (Garrett et al, 2012; Keeler et al, 2015b; Molumby et al, 2016; Suo et al, 2012). We asked whether cortically-restricted Pcdhg mutants also exhibit impaired synapse and dendritic spine development in vivo.…”

“…At these cell-cell contacts, specific cell adhesion molecules initiate target recognition and promote dendrite growth, pre- and postsynaptic differentiation, and mature synaptic function (de Wit and Ghosh, 2016). The 22 γ-Protocadherins (γ-Pcdhs), cadherin superfamily adhesion molecules encoded by the Pcdhg gene cluster, are predominantly expressed in the central nervous system (CNS) and play critical roles during neural development (Reviewed in Keeler et al, 2015a; Mah and Weiner, 2016). The individual γ-Pcdh isoforms (12 “A” subfamily, 7 “B” subfamily, and 3 “C” subfamily members) engage in promiscuous cis multimerization, but interact strictly homophilically in trans (Rubinstein et al, 2015; Schreiner and Weiner, 2010; Thu et al, 2014).…”

Regulation of neural circuit formation by protocadherins

“…Keeler et al [96] identified a serine residue within the γ-Pcdh constant domain that is phosphorylated by PKC in vitro and in vivo; this phosphorylation reduces γ-Pcdh-mediated FAK inhibition, providing a potential feedback mechanism. Overexpression of a non-phosphorylatable (S/A mutant) γ-Pcdh isoform in cortical neurons can increase dendrite arborization cell-autonomously, while overexpression of a phosphomimetic (S/D mutant) isoform, or treatment with the PKC activator PMA, can reduce dendrite arborization [96]. This raises the intriguing possibility that homophilic trans- interaction might lead to conformational changes preventing phosphorylation (or encouraging dephosphorylation) of the γ-Pcdh constant domain, though this remains to be shown experimentally.…”

Genomic responses to selection for tame/aggressive behaviors in the silver fox (Vulpes vulpes)

“…Protocadherins are known to play critical roles in the establishment and function of 93 specific cell-cell connections in the brain, such as synapse development (24) and dendrite 94 arborization and self-avoidance in central nervous system (25,26). Pcdhga1 expression 95 was down-regulated in a learned helpless rat model, suggesting its expression might 96 affect behavior phenotypes (27).…”