The Calcineurin-binding Protein Cain Is a Negative Regulator of Synaptic Vesicle Endocytosis

Lai, Michael M.; Luo, Hongbo; Burnett, Patrick; Hong, Jenny J.; Snyder, Solomon H.

doi:10.1074/jbc.c000429200

Cited by 59 publications

(47 citation statements)

References 29 publications

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“…CAIN (also known as Cabdin) acts as a physiological non-competitive inhibitor of calcineurin and both proteins are components of the endocytotic machinery [50]. Overexpression of CAIN in HEK293 cells blocked endocytosis [51].…”

Section: Discussionmentioning

confidence: 99%

Cytokines activate genes of the endocytotic pathway in insulin-producing RINm5F cells

et al. 2004

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Aims/hypothesis. Cytokines are important humoral mediators of beta cell destruction in autoimmune diabetes. The aim of this study was to identify novel cytokine-induced genes in insulin-producing RINm5F cells, which may contribute to beta cell death or survival. Methods. A global gene expression profile in cytokine-exposed insulin-producing RINm5F cells was achieved by automated restriction fragment differential display PCR. The expression of selected candidate genes was confirmed by real-time RT-PCR analysis. Results. Exposure of RINm5F cells to IL-1β or to a cytokine mixture (IL-1β, TNF-α, IFN-γ) for 6 h resulted in the differential expression of a functional gene cluster. Apart from the well-known up-regulation of the cytokine-responsive genes iNOS, NF-κB, MnSOD and Hsp70, several genes that belong to the functional cluster of the endocytotic pathway were identified. These endocytotic genes comprised: clathrin, megalin, synaptotagmin and calcineurin, which were up-regulated by IL-1β or the cytokine mixture.In contrast, the expression of the calcineurin inhibitor CAIN and of the GDP/GTP exchange protein Rab3 was down-regulated by cytokines. Other up-regulated cytokine-responsive genes were: agrin, murine adherent macrophage protein mRNA (MAMA) and transport-associated protein (TAP1/MTP), whereas the plasma membrane calcium ATPase (PMCA) 2 and PMCA 3 genes were down-regulated by cytokines. Conclusions/interpretation. Our results indicate that genes of the endocytotic pathway are regulated by pro-inflammatory cytokines. This might affect the density of cytokine receptors at the beta cell surface and concomitantly the sensitivity of the cells to cytokine toxicity. A better understanding of the functional cross-talk between endocytotic and cytokine signalling pathways could further the development of novel strategies to protect pancreatic beta cells against toxic effects of pro-inflammatory cytokines.

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Section: Discussionmentioning

confidence: 99%

Cytokines activate genes of the endocytotic pathway in insulin-producing RINm5F cells

et al. 2004

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“…Nonetheless, our experiments highlight the util- ity of this reagent as a cell-based modulator of PP2B. Likewise, Cain has also been used to perturb PP2B function inside cells, as it binds the endocytic machinery through amphiphysin 1 to negatively regulate PP2B/dynamin-dependent synaptic vesicle endocytosis (30,32). Thus it is tempting to speculate that AKAP79 anchoring and inhibition of PP2B might function in a concerted manner to modulate not only AMPA receptor currents but also to attenuate the phosphorylation events that control receptor endocytosis.…”

Section: Discussionmentioning

confidence: 99%

“…For example, the organization of serines, threonines, and the clustering of basic amino acids in this region is reminiscent of the 38-residue PP2B-binding region in Cain, (calcineurin inhibitor)/ cabin (30,31). Both proteins are non-competitive inhibitors of PP2B activity that inhibit the phosphatase in the low micromolar range and bind PP2B at a site distinct from the immunosuppressant drugs FK506 and cyclosporin A (13,17,32). Another common characteristic is the presence of a loosely conserved "PIXIXIT" motif (where X represents any amino acid).…”

Section: Discussionmentioning

confidence: 99%

Mapping the Protein Phosphatase-2B Anchoring Site on AKAP79

Dell’Acqua

Dodge

Tavalin

et al. 2002

Journal of Biological Chemistry

132

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Compartmentalization of protein kinases and phosphatases with substrates is a means to increase the efficacy of signal transduction events. The A-kinase anchoring protein, AKAP79, is a multivalent anchoring protein that maintains the cAMP-dependent protein kinase, protein kinase C, and protein phosphatase-2B (PP2B/calcineurin) at the postsynaptic membrane of excitatory synapses where it is recruited into complexes with Nmethyl-D-aspartic acid or ␣-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-subtype glutamate receptors. We have used cellular targeting of AKAP79 truncation and deletion mutants as an assay to map the PP2B-binding site on AKAP79. We demonstrate that residues 315-360 are necessary and sufficient for AKAP79-PP2B anchoring in cells. Multiple determinants contained within this region bind directly to the A subunit of PP2B and inhibit phosphatase activity. Peptides spanning the 315-360 region of AKAP79 can antagonize PP2B anchoring in vitro and targeting in transfected cells. Electrophysiological experiments further emphasize this point by demonstrating that a peptide encompassing residues 330 -357 of AKAP79 attenuates PP2B-dependent down-regulation of GluR1 receptor currents when perfused into HEK293 cells. We propose that the structural features of this AKAP79-PP2B-binding domain may share similarities with other proteins that serve to coordinate PP2B localization and activity.The efficient transmission of cellular signals often involves the orientation of signaling proteins in relation to their upstream activators and downstream targets. This is often achieved through association with anchoring and scaffolding proteins that compartmentalize signaling enzymes in distinct subcellular environments (1-3). For example, A-kinase anchoring proteins (AKAPs) 1 bind the regulatory (R) subunit of the cAMP-dependent protein kinase (PKA) to localize this broad specificity enzyme to discrete subcellular environments (4, 5). Each AKAP contains a conserved amphipathic helix that binds to the R subunit dimer with high affinity and targeting domains that direct the PKA-AKAP complex to specific subcellular compartments (6, 7). A likely consequence of these proteinprotein interactions is that AKAP-PKA complexes are maintained in the vicinity of selected phosphoproteins and substrates for the kinase. Another important role of AKAPs is to serve as scaffolds for the assembly of multiprotein complexes that include PKA, other protein kinases, phosphodiesterases, and a variety of protein phosphatases (8). The simultaneous anchoring of kinases and phosphatases provides an efficient means to confer bi-directional control on the phosphorylation status of substrate proteins (9, 10).A number of studies (11) have demonstrated that anchoring of kinases and phosphatases ensures the efficient regulation of ion channels and neurotransmitter receptors. One prominent mediator of this process is the multivalent anchoring protein AKAP79 that anchors PKA, protein kinase C (PKC), and protein phosphatase-2B (PP2B/calcineurin) (12...

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“…In mature animals, Cabin1 acts as a calcium-dependent repressor of calcineurin (protein phosphatase 3) in the CNS (Lai et al, 1998(Lai et al, , 2000 and a repressor of both calcineurin and MEF2 (MADS/myocyte enhancer factor 2) in activated Tcells (Youn et al, 1999;Jang et al, 2007a). The MEF2 proteins were originally described as transcription factors required for muscle differentiation, but have since been found to play diverse roles in the CNS (Shalizi and Bonni, 2005 review).…”

Section: Introductionmentioning

confidence: 99%

Cabin1 expression suggests roles in neuronal development

Hammond

Udvadia

2010

Developmental Dynamics

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*Nervous system assembly and function depends on precise regulation of developmental gene expression. Cabin1, an essential gene in developing mice, is enriched in regions of the developing zebrafish central nervous system (CNS). Cabin1 is a repressor of MEF2-(myocyte enhancer factor 2) and calcineurin-mediated transcription in the immune system, but its function in the CNS during development is unknown. We identified Cabin1 from a library of genes enriched in developing neurons and determined the temporal and spatial expression of Cabin1 mRNA during CNS development. We found Cabin1 mRNA expression in the developing brain at times correlated with later aspects of neuronal differentiation. In some regions of the CNS Cabin1 expression overlaps with regions that also express proteins known to interact with Cabin1: MEF2 and/or calcineurin. We suggest that Cabin1 could act as a regulator of MEF2 and calcineurin activity in the developing nervous system, given their roles in neuronal differentiation and synaptic refinement. Developmental Dynamics 239:2443-2451,

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The Calcineurin-binding Protein Cain Is a Negative Regulator of Synaptic Vesicle Endocytosis

Cited by 59 publications

References 29 publications

Cytokines activate genes of the endocytotic pathway in insulin-producing RINm5F cells

Cytokines activate genes of the endocytotic pathway in insulin-producing RINm5F cells

Mapping the Protein Phosphatase-2B Anchoring Site on AKAP79

Cabin1 expression suggests roles in neuronal development

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