Contactin‐associated protein (Caspr) 2 interacts with carboxypeptidase E in the CNS

Oiso, Shigeru; Takeda, Yasuo; Futagawa, Toshitaka; Miura, Takehiko; Kuchiiwa, Satoshi; Nishida, Kazuhiro; Ikeda, Ryuji; Kariyazono, Hiroko; Watanabe, Kazutada; Yamada, Katsushi

doi:10.1111/j.1471-4159.2009.05928.x

Cited by 16 publications

(11 citation statements)

References 38 publications

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“…GluA1 (synaptic membrane protein) was highly enriched in the crude membrane (S5), and synaptic (S6) fractions while PSD95 (synaptic cytosolic protein) was only enriched in the S6 fraction; β‐tubulin (nonsynaptic cytosolic protein) was absent from either S5 or S6 fractions (Figure b, bottom). We found both PAR3 and CNTNAP2 in the S6 (synaptic) fraction, consistent with previous publications (Chen et al, ; Gao et al, ; Lin et al, ; Oiso et al, ). We also validated previous studies and showed strong colocalization of PAR3 with PSD95 (Figure S1).…”

Section: Resultssupporting

confidence: 93%

CNTNAP2 is targeted to endosomes by the polarity protein PAR3

Gao

Pratt

Yoon

et al. 2019

Eur J of Neuroscience

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A decade of genetic studies has established contactin‐associated protein‐like 2 (CNTNAP2) as a prominent susceptibility gene associated with multiple neurodevelopmental disorders. The development and characterization of Cntnap2 knockout models in multiple species have bolstered this claim by establishing clear connections with certain endophenotypes. Despite these remarkable in vivo findings, CNTNAP2’s molecular functions are relatively unexplored, highlighting the need to identify novel protein partners. Here, we characterized an interaction between CNTNAP2 and partitioning‐defective 3 (PAR3)—a polarity molecule isolated in a yeast two‐hybrid screen with CNTNAP2’s C‐terminus. We provide evidence that the two proteins interact via PDZ domain‐mediated binding, that CNTNAP2+/PAR3+ complexes are largely associated with clathrin‐coated endocytic vesicles in heterologous cells and that PAR3 causes an enlargement of CNTNAP2 puncta size. Live imaging and fluorescence recovery after photobleaching (FRAP) reveals that PAR3 limits the mobility of CNTNAP2. Finally, overexpression of PAR3 but not a PAR3 mutant lacking all PDZ domains (PAR3∆PDZall) can cluster endogenous CNTNAP2 in primary neurons. Collectively, we conclude that PAR3 regulates CNTNAP2 spatial localization.

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Section: Resultssupporting

confidence: 93%

CNTNAP2 is targeted to endosomes by the polarity protein PAR3

Gao

Pratt

Yoon

et al. 2019

Eur J of Neuroscience

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“…GluA1 (synaptic membrane protein) was highly enriched in the crude membrane (S5) and synaptic (S6) fractions while PSD95 (synaptic cytosolic protein) was only enriched in the S6 fraction; beta-tubulin (non-synaptic cytosolic protein) was absent from either S5 or S6 fractions (Figure 2b, bottom). We found both Par3 and CNTNAP2 in the S6 fraction, consistent with previous publications (Chen et al, 2015;Oiso et al, 2009;Gao et al, 2018;Lin et al, 2000). Moreover, Par3 was also highly enriched in the crude membraneassociated (S3) fraction but almost nonexistent in S5, while Cntnap2 was most abundant in the S5 fraction, as expected.…”

Section: Subcellular Compartmentalization Of Par3 and Cntnap2supporting

confidence: 92%

CNTNAP2 is targeted to endosomes by the polarity protein Par3

Gao

Pratt

Yoon

et al. 2019

Preprint

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A decade of genetic studies has established Contactin-associated protein-like 2 (CNTNAP2 ) as a prominent susceptibility gene associated with multiple neurodevelopmental disorders. The development and characterization of Cntnap2 knockout models in multiple species have bolstered this claim by establishing clear connections with certain endophenotypes. Despite these remarkable in vivo findings, CNTNAP2's molecular functions are relatively unexplored, highlighting the need to identify novel protein partners. Here, we characterized an interaction between CNTNAP2 and Partitioning-defective 3 (Par3) -a polarity molecule we isolated in a yeast-two hybrid screen with CNTNAP2's Cterminus. We provide evidence that the two proteins interact via PDZ domainmediated binding, that CNTNAP2 + /Par3 + complexes are largely associated with clathrin-coated endocytic vesicles, and that Par3 causes an enlargement of these structures. Live imaging and fluorescence recovery after photobleaching (FRAP) reveals that Par3 limits the mobility of CNTNAP2 at endosomes, thus stabilizing it at that location. Finally, expression of Par3 but not Par3∆PDZ can cluster endogenous CNTNAP2 in primary neurons. Collectively, we conclude * Corresponding author 1 Equal contribution

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“…; Oiso et al . ; Fujita et al . ) and is involved not only in the organization of myelinated axons (Poliak et al .…”

Section: Discussionmentioning

confidence: 99%

“…CASPR2 mutation and the pathogenesis of ASD CASPR2 is expressed in brain regions important for social cognition, language, and implicit learning, such as the frontal cortex, anterior temporal cortex, and basal ganglia (Poliak et al 1999;Peñagarikano and Geschwind 2012). CASPR2 predominantly localizes at dendrites and cell bodies (Poliak et al 1999;Oiso et al 2009;Fujita et al 2011) and is involved not only in the organization of myelinated axons (Poliak et al 2003;Traka et al 2003), but also the development of dendritic arbors and spines in a cellautonomous fashion (Anderson et al 2012).…”

Section: Discussionmentioning

confidence: 99%

CASPR2 forms a complex with GPR37 via MUPP1 but not with GPR37(R558Q), an autism spectrum disorder‐related mutation

Tanabe

Fujita-Jimbo

Momoi

et al. 2015

Journal of Neurochemistry

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Autism spectrum disorder (ASD) is a developmental brain disorder. Mutations in synaptic components including synaptic adhesion molecules have been found in ASD patients. Contactin-associated protein-like 2 (CASPR2) is one of the synaptic adhesion molecules associated with ASD. CASPR2 forms a complex with receptors via interaction with multiple PDZ domain protein 1 (MUPP1). Little is known about the relationship between impaired CASPR2-MUPP1-receptor complex and the pathogenesis of ASD. GPR37 is a receptor for survival factors. We recently identified mutations including R558Q in the G-protein-coupled receptor 37 (GPR37) gene in ASD patients. The mutated GPR37s accumulate in the endoplasmic reticulum. In this study, we show that GPR37 is a component of the CASPR2-MUPP1 receptor complex in the mouse brain. CASPR2 and GPR37 mainly interacted with the PDZ3 and PDZ11 domains of MUPP1, respectively. Compared to GPR37, GPR37(R558Q) slightly interacted with MUPP1 and caused dendritic alteration. GPR37, but not GPR37(R558Q) nor GPR37-deltaC which lacks its PDZ binding domain, was transported to the cell surface by MUPP1. In primary hippocampal neurons, GPR37 co-localized with MUPP1 and CASPR2 at the synapse, but not GPR37(R558Q). Thus, ASD-related mutation of GPR37 may cause the impaired CASPR2-MUPP1-GPR37 complex on the dendrites associated with one of the pathogenesis of ASD. In this study, we identified that GPR37 is a component of the MUPP1 and CASPR2 receptor complex. Autism deleterious mutated GPR37(R558Q) slightly interacts with MUPP1 and retains in ER, resulting in dendritic alteration. In neuron, GPR37, but not GPR37(R558Q), is transported to the dendrite and synapse by MUPP1. Thus, ASD-related mutation of GPR37 may cause the impaired CASPR2-MUPP1-GPR37 complex on the dendrites associated with one of the pathogenesis of ASD.

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Contactin‐associated protein (Caspr) 2 interacts with carboxypeptidase E in the CNS

Cited by 16 publications

References 38 publications

CNTNAP2 is targeted to endosomes by the polarity protein PAR3

CNTNAP2 is targeted to endosomes by the polarity protein PAR3

CNTNAP2 is targeted to endosomes by the polarity protein Par3

CASPR2 forms a complex with GPR37 via MUPP1 but not with GPR37(R558Q), an autism spectrum disorder‐related mutation

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