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Protein Kinase C Phosphorylation of a γ-Protocadherin C-terminal Lipid Binding Domain Regulates Focal Adhesion Kinase Inhibition and Dendrite Arborization
Journal article   Open access   Peer reviewed

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

Austin B Keeler, Dietmar Schreiner and Joshua A Weiner
The Journal of biological chemistry, Vol.290(34), pp.20674-20686
08/21/2015
DOI: 10.1074/jbc.M115.642306
PMCID: PMC4543629
PMID: 26139604
url
https://doi.org/10.1074/jbc.M115.642306View
Published (Version of record) Open Access

Abstract

The γ-protocadherins (γ-Pcdhs) are a family of 22 adhesion molecules with multiple critical developmental functions, including the proper formation of dendritic arbors by forebrain neurons. The γ-Pcdhs bind to and inhibit focal adhesion kinase (FAK) via a constant C-terminal cytoplasmic domain shared by all 22 proteins. In cortical neurons lacking the γ-Pcdhs, aberrantly high activity of FAK and of PKC disrupts dendrite arborization. Little is known, however, about how γ-Pcdh function is regulated by other factors. Here we show that PKC phosphorylates a serine residue situated within a phospholipid binding motif at the shared γ-Pcdh C terminus. Western blots using a novel phospho-specific antibody against this site suggest that a portion of γ-Pcdh proteins is phosphorylated in the cortex in vivo. We find that PKC phosphorylation disrupts both phospholipid binding and the γ-Pcdh inhibition of (but not binding to) FAK. Introduction of a non-phosphorylatable (S922A) γ-Pcdh construct into wild-type cortical neurons significantly increases dendrite arborization. This same S922A construct can also rescue dendrite arborization defects in γ-Pcdh null neurons cell autonomously. Consistent with these data, introduction of a phosphomimetic (S/D) γ-Pcdh construct or treatment with a PKC activator reduces dendrite arborization in wild-type cortical neurons. Together, these data identify a novel mechanism through which γ-Pcdh control of a signaling pathway important for dendrite arborization is regulated.
 Focal Adhesion Kinase 1 - genetics Protein Kinase C - genetics Phosphorylation Tetradecanoylphorbol Acetate - pharmacology Cadherins - metabolism Embryo, Mammalian Myristoylated Alanine-Rich C Kinase Substrate Molecular Sequence Data Dendrites - ultrastructure Intracellular Signaling Peptides and Proteins - metabolism Cerebral Cortex - metabolism Cerebral Cortex - ultrastructure Neurogenesis - genetics Gene Expression Regulation, Developmental Protein Kinase C - metabolism Phosphatidylinositols - metabolism Membrane Proteins - metabolism Cerebral Cortex - drug effects Cadherins - genetics Focal Adhesion Kinase 1 - metabolism Intracellular Signaling Peptides and Proteins - genetics Protein Structure, Tertiary Amino Acid Sequence Dendrites - drug effects Dendrites - metabolism Signal Transduction Membrane Proteins - genetics Mice, Inbred C57BL Animals Cerebral Cortex - growth & development Protein Binding Mice Primary Cell Culture Focal Adhesion Kinase 1 - antagonists & inhibitors Dendrites - genetics

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