Proteolytic processing of protocadherin proteins requires endocytosis

Abstract

The α-, β-, and γ-protocadherins (Pcdhα, Pcdhβ, and Pcdhγ) comprise a large family of single-pass transmembrane proteins predominantly expressed in the nervous system. These proteins contain six cadherin-like extracellular domains, and proteolysis of Pcdhα and Pcdhγ by the γ-secretase complex releases their intracellular domains into the cytoplasm where they may function locally and/ or enter the nucleus and affect gene expression. Thus, cleavage of Pcdhs may function to link intercellular contacts and intracellular signaling. Here we report that shedding of the Pcdhα extracellular domain and subsequent processing by γ-secretase require endocytosis and that Pcdhs interact with the regulator of vesicular sorting ESCRT-0 in undifferentiated cells. We also find that the accumulation of Pcdh cleavage products is regulated during development. Differentiation leads to an increase in the interactions between Pcdh proteins and a decrease in the accumulation of cleavage products. We conclude that Pcdh processing requires endocytosis and that the level of cleavage products is regulated during neuronal differentiation.γ-secretase | hepatocyte growth factor-regulated tyrosine kinase substrate | neurodevelopment | protein-protein interactions | proteolysis

Structural origins of clustered protocadherin-mediated neuronal barcoding

“…The model assumes that this large assembly then produces a signal for the two cells to move apart, with the assembly itself likely destroyed by proteolysis. In fact, the clustered Pcdhs have been shown to be cleaved by a metalloprotease and γ-secretase during development [45, 63–65]. In contrast, when neurites from different neurons come into contact, there will be a high probability of at least one mismatched isoform which is enough to limit assembly size, and no repulsion signal will be produced.…”

The very many faces of presenilins and the γ-secretase complex

“…It has been demonstrated that the γ-secretase-dependent cleavage of Pcdhα requires endocytosis. There were also suggestions that in this case, endocytosis of Pcdhα, extracellular domain cleavage, γ-secretase cleavage, and ESCRT-dependent trafficking maybe co-regulated during differentiation (Buchanan et al 2010). Interestingly, the endosomal sorting complex (ESCRT) also directs Notch-positive endosomes to the multivesicular body pathway and the lysosome (Vaccari et al 2008).…”

“…An elegant example linking: γ-secretase cleavage, signaling and endocytosis, is the proteolytic processing of protocadherin proteins (Pcdh; Buchanan et al 2010). Protocadhedrins are single-pass transmembrane proteins predominantly expressed in the nervous system.…”

Transcriptional Regulation of the Protocadherin β Cluster during Her-2 Protein-induced Mammary Tumorigenesis Results from Altered N-Glycan Branching

“…Like the classic cadherins, Pcdhs are glycoproteins with N-linked glycan sequons located in their extracellular domains. Studies have shown that Pcdhs are proteolytically cleaved by ␥-secretase complex, producing soluble intracellular fragments that may enter the nucleus and affect gene expression (41,42). Of note, several studies have shown that the Pcdh superfamily may be implicated in tumor development and function as tumor suppressors.…”