Immunophilins in the Nervous System

Snyder, Solomon H.; Lai, Michael M.; Burnett, Patrick

doi:10.1016/s0896-6273(00)80538-3

Cited by 195 publications

(131 citation statements)

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“…The ERK͞MAP kinase pathway, acting through Ras leads to phosphorylation of MAP kinase͞Erk kinase, which in turn phosphorylates MAP kinase, which translocates to the nucleus leading to the phosphorylation of transcription factor CREB (2). The p38 pathway is activated via interactions of TAK1 binding protein (TAB1) with TGF␤-activated kinase 1 (TAK1) leading to the phosphorylation and activation of p38, which can translocate to the nucleus and phosphorylate multiple targets both in the cytosol and nucleus (3). The SMAD pathway is initiated by TGF-␤ RI binding to and phosphorylating SMAD2͞3, which then binds to SMAD4 leading to translocation of the SMAD complex into the nucleus.…”

Section: Discussionmentioning

confidence: 99%

“…Although first identified in immune cells, FKBP12 occurs in all tissues, with particularly high densities in the brain, and appears to have diverse functions, which have been only partially characterized (3). FKBP12 is a subunit of two intracellular calcium release channels, the inositol 1,4,5-trisphosphate receptor and the ryanodine receptor (4,5), and is also a subunit of the TGF-␤ type I receptor (6,7).…”

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confidence: 99%

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FKBP12, the 12-kDa FK506-binding protein, is a physiologic regulator of the cell cycle

Aghdasi

Resnick

et al. 2001

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

130

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FKBP12, the 12-kDa FK506-binding protein, is a ubiquitous abundant protein that acts as a receptor for the immunosuppressant drug FK506, binds tightly to intracellular calcium release channels and to the transforming growth factor ␤ (TGF-␤) type I receptor. We now demonstrate that cells from FKBP12-deficient (FKBP12 ؊/؊ ) mice manifest cell cycle arrest in G1 phase and that these cells can be rescued by FKBP12 transfection. This arrest is mediated by marked augmentation of p21(WAF1͞CIP1) levels, which cannot be further augmented by TGF-␤1. The p21 up-regulation and cell cycle arrest derive from the overactivity of TGF-␤ receptor signaling, which is normally inhibited by FKBP12. Cell cycle arrest is prevented by transfection with a dominant-negative TGF-␤ receptor construct. TGF-␤ receptor signaling to gene expression can be mediated by SMAD, p38, and ERK͞MAP kinase (extracellular signalregulated kinase͞mitogen-activated protein kinase) pathways. SMAD signaling is down-regulated in FKBP12 ؊/؊ cells. Inhibition of ERK͞MAP kinase fails to affect p21 up-regulation. By contrast, activated phosphorylated p38 is markedly augmented in FKBP12 ؊/؊ cells and the p21 up-regulation is prevented by an inhibitor of p38. Thus, FKBP12 is a physiologic regulator of cell cycle acting by normally down-regulating TGF-␤ receptor signaling.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

FKBP12, the 12-kDa FK506-binding protein, is a physiologic regulator of the cell cycle

Aghdasi

Resnick

et al. 2001

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

130

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“…The immunosuppressant drugs cyclosporin A and FK506 are known inhibitors of calcineurin (20,21). Treatment with cyclosporin A or FK506 reduces endocytosis to the same extent as does cain overexpression (Table I).…”

Section: Cain Inhibits Endocytosis 34018mentioning

confidence: 99%

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

Lai

Luo

Burnett

et al. 2000

Journal of Biological Chemistry

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During neurotransmitter release, exocytosed neurotransmitter vesicles are recycled by endocytosis, which involves the assembly of a complex of endocytic proteins. Assembly of endocytic proteins into a functional complex depends on their dephosphorylation by calcineurin, a calcium-sensitive protein phosphatase and the inhibitory target of immunosuppressive drugs cyclosporin A and FK506. Cain is a recently identified protein inhibitor of calcineurin. We now provide evidence that cain is a component of the endocytic protein complex. The proline-rich region of cain forms a stable association with the SH3 domain of amphiphysin 1. Using a transferrin uptake assay, we found that overexpression of cain in HEK293 cells blocks endocytosis as potently as expression of a dominant negative dynamin 1 construct. The use of other calcineurin inhibitors such as cyclosporin A and FK506 also blocks endocytosis. Since binding of cain to amphiphysin 1 does not affect amphiphysin's interaction with other endocytic proteins, our results suggest that cain negatively regulates synaptic vesicle endocytosis by inhibiting calcineurin activity, rather than sterically interfering with the assembly of the endocytic protein complex.

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“…FK506, a lipid‐soluble immunosuppressant used to prevent transplant rejection,8 partitions well into the central nervous system (CNS). FK506 interferes with calcineurin phosphatase activity via FK‐binding protein 12, leading to decreased activation of inflammatory genes regulated by the transcription factor NFAT,8, 9, 10 and thereby inhibits T cell function 9…”

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confidence: 99%

A destructive feedback loop mediated by CXCL10 in central nervous system inflammatory disease

Roberts

Blachère

Frank

et al. 2015

Annals of Neurology

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ObjectiveParaneoplastic neurologic disorders (PND) are autoimmune diseases associated with cancer and ectopic expression of a neuronal antigen in a peripheral tumor. Patients with PND harbor high‐titer antibodies and T cells in their serum and cerebrospinal fluid (CSF) that are specific to the tumor antigen, and treatment with the immunosuppressant FK506 (tacrolimus) decreases CSF white blood cell counts. The objective of this study was to determine the effect of FK506 on CSF chemokine levels in PND patients.MethodsCSF samples before and after FK506 treatment were tested by multiplex assay for the presence of 27 cytokines. Follow‐up in vitro experiments aimed to determine whether T cells secrete CXCL10 in response to cognate antigen.ResultsHere we report that PND patients harbor high levels of the chemokine CXCL10 in their CSF. CXCL10 is a cytokine that recruits CXCR3+ cells such as activated T cells, and we found that FK506 treatment specifically decreased CSF CXCL10 from among 27 cytokines tested. In vitro, CXCL10 was only produced during antigen‐specific cognate interactions between T cells and antigen‐presenting cells (APCs) when interferon‐γ (IFNγ) receptors were present on the T cell.InterpretationThese results support a model in which antigen‐specific T cell stimulation by PND APCs triggers IFNγ, followed by CXCL10 production and further lymphocyte recruitment, suggesting that treatments targeting T cells or CXCL10 in the central nervous system (CNS) may interrupt a destructive positive feedback loop present in CNS inflammation. Ann Neurol 2015;78:619–629

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Immunophilins in the Nervous System

Abstract: The first important insight into how immunosuppres-School of Medicine sants act came with the observation by Handschumacher Johns Hopkins University and associates (1984) that CsA binds to a cytoplasmic Baltimore, Maryland 21205 18 kDa protein designated cyclophilin A. Subsequently,

Cited by 195 publications

References 100 publications

FKBP12, the 12-kDa FK506-binding protein, is a physiologic regulator of the cell cycle

FKBP12, the 12-kDa FK506-binding protein, is a physiologic regulator of the cell cycle

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

A destructive feedback loop mediated by CXCL10 in central nervous system inflammatory disease

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