Interaction with Protocadherin-γ Regulates the Cell Surface Expression of Protocadherin-α

Murata, Yoji; Hamada, Shin; Morishita, Hirofumi; Mutoh, Tetsuji; Yagi, Takeshi

doi:10.1074/jbc.m408771200

Cited by 104 publications

(121 citation statements)

References 27 publications

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“…3B). This result is in agreement with a report that the extracellular domains are required for Pcdh interactions (9). Strikingly, upon differentiation, CTF1 derived from Pcdhα4ΔEC1-5 is present at undifferentiated levels (Fig.…”

Section: Resultssupporting

confidence: 82%

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Proteolytic processing of protocadherin proteins requires endocytosis

Buchanan

Schalm

Maniatis

2010

Proc. Natl. Acad. Sci. U.S.A.

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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

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Section: Resultssupporting

confidence: 82%

“…Their extracellular domains have the capacity to interact with each other both homophilically and heterophilically (7)(8)(9). However, their interactions are much weaker than those of the classic cadherins such as N-cadherin (N-Cad) (10).…”

mentioning

confidence: 99%

Proteolytic processing of protocadherin proteins requires endocytosis

Buchanan

Schalm

Maniatis

2010

Proc. Natl. Acad. Sci. U.S.A.

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“…In addition, Pcdhs and Ret localize to endosomes and the cell surface (24,31), and we detected Pcdhα4-TAP and Pcdhγ7-TAP colocalization in a punctate pattern along processes in CAD cells (Fig. 1D).…”

Section: Discussionmentioning

confidence: 90%

Phosphorylation of protocadherin proteins by the receptor tyrosine kinase Ret

Schalm

Ballif

Buchanan

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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The clustered protocadherins (Pcdhs) are a large family of cadherinlike transmembrane proteins expressed in the nervous system. Stochastic expression of Pcdh genes and alternative splicing of their pre-mRNAs have the potential to generate enormous protein diversity at the cell surface of neurons. At present, the regulation and function of Pcdh proteins are largely unknown. Here, we show that Pcdhs form a heteromeric signaling complex(es), consisting of multiple Pcdh isoforms, receptor tyrosine kinases, phosphatases, and cell adhesion molecules. In particular, we find that the receptor tyrosine kinase rearranged during transformation (Ret) binds to Pcdhs in differentiated neuroblastoma cells and is required for stabilization and differentiation-induced phosphorylation of Pcdh proteins. In addition, the Ret ligand glial cell line-derived neurotrophic factor induces phosphorylation of Pcdhγ in motor neurons and phosphorylation of Pcdhα and Pcdhγ in sympathetic neurons. Conversely, Pcdh proteins are also required for the stabilization of activated Ret in neuroblastoma cells and sympathetic ganglia. Thus, Pcdhs and Ret are functional components of a phosphorylationdependent signaling complex. intracellular domain | signal transduction | TAP tag | protein-protein interactions | protein purification

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“…Interestingly, the C-type variable exons were constantly expressed in Purkinje cells at postnatal day (P) 3 21 from both alleles, although monoallelic and combinatorial types of expression were commonly found for the Pcdh-␣, Pcdh-␥A, and Pcdh-␥B variable exons. Our results indicated that biallelic and monoallelic gene regulation for variable exons coexist for each Pcdh gene cluster.…”

mentioning

confidence: 99%

Allelic Gene Regulation of Pcdh-α and Pcdh-γ Clusters Involving Both Monoallelic and Biallelic Expression in Single Purkinje Cells

Kaneko

Kato

Kawamura

et al. 2006

Journal of Biological Chemistry

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The molecular basis for providing the identity and diversity of single neurons is a key for realizing the brain system. Diverse protocadherin isoforms encoded by the Pcdh-␣ and Pcdh-␥ gene clusters are expressed in all of the vertebrates studied. For the Pcdh-␣ isoforms, differential expression patterns have been found in single Purkinje cells by unusual monoallelic and combinatorial types of gene regulation. Here we investigated total allelic gene regulation in the Pcdh-␣ and -␥ clusters, including the C-type variable exons (C1 to C5) and the Pcdh-␥A and -␥B variable exons in single Purkinje cells. Using split single-cell reverse transcription-PCR analysis, almost all of the Purkinje cells at postnatal day 21 biallelically expressed all the C-type isoforms, whereas the Pcdh-␣ isoforms showed both monoallelic and combinatorial expression. The Pcdh-␥A and -␥B isoforms also showed differential regulation in each cell with both monoallelic and combinatorial gene regulation. These data indicated that different types of allelic gene regulation (monoallelic versus biallelic) occurred in the Pcdh-␣ and -␥ clusters, although they were spliced into the same constant exons. It has been reported that each C-type Pcdh-␣ or -␥ transcript has a different expression pattern during brain development, suggesting that the different C-type variable exons may code temporal diversity, although the Pcdh-␣, -␥A, and -␥B isoforms were differential and combinatorial gene regulation within a single cell. Thus, the multiple gene regulations in the Pcdh-␣ and -␥ clusters had a potential mechanism for increasing the diversity of individual neurons in the brain.

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Interaction with Protocadherin-γ Regulates the Cell Surface Expression of Protocadherin-α

Cited by 104 publications

References 27 publications

Proteolytic processing of protocadherin proteins requires endocytosis

Proteolytic processing of protocadherin proteins requires endocytosis

Phosphorylation of protocadherin proteins by the receptor tyrosine kinase Ret

Allelic Gene Regulation of Pcdh-α and Pcdh-γ Clusters Involving Both Monoallelic and Biallelic Expression in Single Purkinje Cells

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