Phosphorylation of protocadherin proteins by the receptor tyrosine kinase Ret

Schalm, Stefanie; Ballif, Bryan A.; Buchanan, Sean M.; Phillips, Greg R.; Maniatis, Tom

doi:10.1073/pnas.1007182107

Cited by 56 publications

(62 citation statements)

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“…Neuronal activity may therefore allow an increase in CTF levels in mature cells. Additionally, we find that in mature neurons and differentiated CAD cells, the Pcdhs bind to the receptor tyrosine kinase Ret and participate in GDNF-inducible signaling that is independent of γ-secretase cleavage (18). Therefore, in differentiated neuronal cells, the Pcdhs may be poised for both cleavage-dependent and cleavage-independent signaling.…”

Section: Discussionmentioning

confidence: 90%

“…Mutations in the Pcdhα gene cluster do not appear to affect cell viability or synapse number, but have been reported to disrupt the formation of proper glomeruli in the olfactory bulb and the innervation of target areas by serotonergic neurons (15,16). In addition, both Pcdhα and -γ have been shown to bind to each other and the tyrosine kinases PYK2, FAK (17), and Ret (18) and to a variety of other signaling molecules. Thus, Pcdhs function, at least in part, by linking intercellular contacts to intracellular signaling pathways.…”

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confidence: 99%

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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: Discussionmentioning

confidence: 90%

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confidence: 99%

Proteolytic processing of protocadherin proteins requires endocytosis

Buchanan

Schalm

Maniatis

2010

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

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“…Although the intracellular domains encoded by the constant exons of the Pcdha and Pcdhg clusters differ significantly from each other, they are strictly conserved in vertebrate evolution, suggesting a conserved cellular function. Both Pcdha and Pcdhg proteins bind the receptor tyrosine kinase Ret, which is required for the stabilization and phosphorylation of their intracellular domains (Schalm et al, 2010). Glial cell line-derived neurotrophic factor (GDNF), a ligand of the Ret receptor, induces the phosphorylation of Pcdhs in cultured motoneurons and sympathetic neurons.…”

Section: Homophilic Interactions and Intracellular Signalingmentioning

confidence: 99%

“…These interactions have been implicated in the defects in cell survival and dendritic patterning observed in Pcdha-or Pcdhg-deficient neurons (Chen et al, 2009; Garrett et al, 2012;Suo et al, 2012). A large number of other potential interacting proteins, including phosphatases, kinases, adhesion molecules and synaptic proteins, have been reported (Han et al, 2010;Schalm et al, 2010), suggesting that clustered Pcdhs may form large heteromeric complexes with broad functions yet to be elucidated.The role of clustered Pcdhs in intracellular signaling is further supported by the finding that they are proteolytically processed by the γ-secretase complex, which releases soluble intracellular fragments into the cytoplasm (Haas et al, 2005; Hambsch et al, 2005;Reiss et al, 2006; Bonn et al, 2007;Buchanan et al, 2010). This process, which requires endocytosis, is developmentally regulated, and a decrease in cleavage products is observed upon neuronal differentiation (Buchanan et al, 2010).…”

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Clustered protocadherins

Chen

Maniatis²

2013

Development

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The majority of vertebrate protocadherin (Pcdh) genes are clustered in a single genomic locus, and this remarkable genomic organization is highly conserved from teleosts to humans. These clustered Pcdhs are differentially expressed in individual neurons, they engage in homophilic trans-interactions as multimers and they are required for diverse neurodevelopmental processes, including neurite self-avoidance. Here, we provide a concise overview of the molecular and cellular biology of clustered Pcdhs, highlighting how they generate single cell diversity in the vertebrate nervous system and how such diversity may be used in neural circuit assembly.Key words: CTCF, Cohesin, Promoter choice, Single cell diversity, Homophilic interaction, Self-avoidance Introduction Protocadherins (Pcdhs), which are predominantly expressed in the nervous system, constitute the largest subfamily of the cadherin superfamily of cell-adhesion molecules. The founding members of the Pcdh gene family were discovered by Suzuki and co-workers in an effort to isolate novel cadherin repeat-containing genes (Sano et al., 1993). Distinct Pcdh members were subsequently cloned, and these included a set of eight cDNAs encoding cadherin-related neuronal receptors (CNRs) (Kohmura et al., 1998). A striking characteristic of the corresponding CNR mRNAs is that their 5Ј ends are distinct, whereas their 3Ј ends are all identical, suggesting that they are generated by alternative pre-mRNA splicing. Characterization of the human genomic DNA encoding the CNR mRNAs revealed that they are encoded in a large Pcdh gene cluster designated α (Pcdha), which is located immediately upstream of two additional Pcdh gene clusters designated β (Pcdhb) and γ (Pcdhg) (Wu and Maniatis, 1999). Remarkably, the genomic organization of the Pcdh gene clusters resembles that of the immunoglobulin and T-cell receptor genes, both of which generate enormous diversity in the immune system through a mechanism that Development 140, 3297-3302 (2013) DEVELOPMENT 3298 involves somatic cell DNA rearrangement. Subsequent studies confirmed the possibility that the clustered Pcdhs serve as a source of molecular diversity in the nervous system, albeit through a different mechanism. The enormous cell surface diversity resulting from the combinatorial expression of Pcdh isoforms, together with the extraordinary specificity afforded by their homophilic interactions, have led to the speculation that clustered Pcdhs are functional counterparts of the Drosophila Dscam1 proteins, which play a central role in neural circuit assembly in the invertebrate nervous system (Zipursky and Sanes, 2010). Indeed, recent studies have demonstrated that the Pcdhg gene cluster is required for neurite self-avoidance in the mouse, in a manner similar to that of the Dscam1 gene in the fly (Lefebvre et al., 2012). Thus, it appears that clustered Pcdhs may function as molecular barcodes for selfrecognition by individual neurons in the vertebrate nervous system. Here, we briefly review studies that led to this hypothesis...

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Expression of protocadherin‐γC4 protein in the rat brain

Miralles

Taylor

Bear

et al. 2019

J of Comparative Neurology

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It has been proposed that the combinatorial expression of γ‐protocadherins (Pcdh‐γs) and other clustered protocadherins (Pcdhs) provides a code of molecular identity and individuality to neurons, which plays a major role in the establishment of specific synaptic connectivity and formation of neuronal circuits. Particular attention has been directed to the Pcdh‐γ family, for which experimental evidence derived from Pcdh‐γ‐deficient mice shows that they are involved in dendrite self‐avoidance, synapse development, dendritic arborization, spine maturation, and prevention of apoptosis of some neurons. Moreover, a triple‐mutant mouse deficient in the three C‐type members of the Pcdh‐γ family (Pcdh‐γC3, Pcdh‐γC4, and Pcdh‐γC5) shows a phenotype similar to the mouse deficient in whole Pcdh‐γ family, indicating that the latter is largely due to the absence of C‐type Pcdh‐γs. The role of each individual C‐type Pcdh‐γ is not known. We have developed a specific antibody to Pcdh‐γC4 to reveal the expression of this protein in the rat brain. The results show that although Pcdh‐γC4 is expressed at higher levels in the embryo and earlier postnatal weeks, it is also expressed in the adult rat brain. Pcdh‐γC4 is expressed in both neurons and astrocytes. In the adult brain, the regional distribution of Pcdh‐γC4 immunoreactivity is similar to that of Pcdh‐γC4 mRNA, being highest in the olfactory bulb, dentate gyrus, and cerebellum. Pcdh‐γC4 forms puncta that are frequently apposed to glutamatergic and GABAergic synapses. They are also frequently associated with neuron‐astrocyte contacts. The results provide new insights into the cell recognition function of Pcdh‐γC4 in neurons and astrocytes.

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Phosphorylation of protocadherin proteins by the receptor tyrosine kinase Ret

Cited by 56 publications

References 34 publications

Proteolytic processing of protocadherin proteins requires endocytosis

Proteolytic processing of protocadherin proteins requires endocytosis

Clustered protocadherins

Expression of protocadherin‐γC4 protein in the rat brain

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