Significance of Calcium Binding, Tyrosine Phosphorylation, and Lysine Trimethylation for the Essential Function of Calmodulin in Vertebrate Cells Analyzed in a Novel Gene Replacement System

Panina, Svetlana; Stephan, Alexander; Cour, Jonas M. la; Jacobsen, Kivin; Kallerup, Line K.; Bumbuleviciute, Rasita; Knudsen, Kristoffer V. K.; Sánchez-González, Pablo; Villalobo, Antonio; Olesen, Uffe H.; Berchtold, Martin W.

doi:10.1074/jbc.m112.339382

Cited by 18 publications

(19 citation statements)

References 43 publications

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“…Exogenously expressed CaM lobes may not fully populate the channels and the observed effects may be corrupted by fluctuations in ambient CaM. Similarly, genetic replacement of endogenous CaM with lobe peptides lacks target specificity and impacts cell viability (26). To overcome these limitations, we utilize a two-prong approach: (i) Full-length or individual CaM Significance Calmodulin (CaM) regulation of voltage-gated calcium (Ca V ) channels constitutes a prototypic biological feedback mechanism that contributes prominently toward Ca 2+ homeostasis in neurons and cardiac myocytes.…”

Section: Resultsmentioning

confidence: 99%

Bilobal architecture is a requirement for calmodulin signaling to Ca _V 1.3 channels

Banerjee

Yoder

Yue

et al. 2018

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

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Calmodulin (CaM) regulation of voltage-gated calcium (Ca) channels is a powerful Ca feedback mechanism that adjusts Ca influx, affording rich mechanistic insights into Ca decoding. CaM possesses a dual-lobed architecture, a salient feature of the myriad Ca-sensing proteins, where two homologous lobes that recognize similar targets hint at redundant signaling mechanisms. Here, by tethering CaM lobes, we demonstrate that bilobal architecture is obligatory for signaling to Ca channels. With one lobe bound, Ca carboxy tail rearranges itself, resulting in a preinhibited configuration precluded from Ca feedback. Reconstitution of two lobes, even as separate molecules, relieves preinhibition and restores Ca feedback. Ca channels thus detect the coincident binding of two Ca-free lobes to promote channel opening, a molecular implementation of a logical NOR operation that processes spatiotemporal Ca signals bifurcated by CaM lobes. Overall, a unified scheme of Ca channel regulation by CaM now emerges, and our findings highlight the versatility of CaM to perform exquisite Ca computations.

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Section: Resultsmentioning

confidence: 99%

Bilobal architecture is a requirement for calmodulin signaling to Ca _V 1.3 channels

Banerjee

Yoder

Yue

et al. 2018

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

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“…The absence of methylation has been reported not to affect cell growth and viability in a chicken cell line [28]. However, the methylation status of CaM can vary in a developmentally specific manner [13], [29].…”

Section: Discussionmentioning

confidence: 98%

Human Calmodulin Methyltransferase: Expression, Activity on Calmodulin, and Hsp90 Dependence

et al. 2012

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Deletion of the first exon of calmodulin-lysine N-methyltransferase (CaM KMT, previously C2orf34) has been reported in two multigene deletion syndromes, but additional studies on the gene have not been reported. Here we show that in the cells from 2p21 deletion patients the loss of CaM KMT expression results in accumulation of hypomethylated calmodulin compared to normal controls, suggesting that CaM KMT is essential for calmodulin methylation and there are no compensatory mechanisms for CaM methylation in humans. We have further studied the expression of this gene at the transcript and protein levels. We have identified 2 additional transcripts in cells of the 2p21 deletion syndrome patients that start from alternative exons positioned outside the deletion region. One of them starts in the 2nd known exon, the other in a novel exon. The transcript starting from the novel exon was also identified in a variety of tissues from normal individuals. These new transcripts are not expected to produce proteins. Immunofluorescent localization of tagged CaM KMT in HeLa cells indicates that it is present in both the cytoplasm and nucleus of cells whereas the short isoform is localized to the Golgi apparatus. Using Western blot analysis we show that the CaM KMT protein is broadly expressed in mouse tissues. Finally we demonstrate that the CaM KMT interacts with the middle portion of the Hsp90 molecular chaperon and is probably a client protein since it is degraded upon treatment of cells with the Hsp90 inhibitor geldanamycin. These findings suggest that the CaM KMT is the major, possibly the single, methyltransferase of calmodulin in human cells with a wide tissue distribution and is a novel Hsp90 client protein. Thus our data provides basic information for a gene potentially contributing to the patient phenotype of two contiguous gene deletion syndromes.

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“…Furthermore, the occurrence of CaM/EGFR complexes in living cells was established, and the possible functional implication of this interaction for ligand-dependent activation of the receptor was determined (66)(67)(68)(69)(70)(71). The recent engineering of vertebrate conditional CaM-knockout cell lines (72) has been an important breakthrough to obtain further evidence of the positive regulatory action that the Ca 2+ /CaM complex exerts on the liganddependent activation of the EGFR in living cells without the need to use CaM antagonists, as these compounds could have unwanted off-target side effects (73).…”

Section: Erbb Receptors and Calmodulinmentioning

confidence: 99%

Targeting the Calmodulin-Regulated ErbB/Grb7 Signaling Axis in Cancer Therapy

et al. 2013

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Signal transduction pathways essential for the survival and viability of the cell and that frequently present aberrant expression or function in tumors are attractive targets for pharmacological intervention in human cancers. In this short review we will describe the regulation exerted by the calcium-receptor protein calmodulin (CaM) on signaling routes involving the family of ErbB receptors - highlighting the epidermal growth factor receptor (EGFR/ErbB1) and ErbB2 - and the adaptor protein Grb7, a downstream signaling component of these receptors. The signaling mechanism of the ErbB/Grb7 axis and the regulation exerted by CaM on this pathway will be described. We will present a brief overview of the current efforts to inhibit the hyperactivity of ErbB receptors and Grb7 in tumors. The currently available information on targeting the CaM-binding site of these signaling proteins will be analyzed, and the pros and cons of directly targeting CaM versus the CaM-binding domain of the ErbB receptors and Grb7 as potential anti-cancer therapy will be discussed. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

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Significance of Calcium Binding, Tyrosine Phosphorylation, and Lysine Trimethylation for the Essential Function of Calmodulin in Vertebrate Cells Analyzed in a Novel Gene Replacement System

Cited by 18 publications

References 43 publications

Bilobal architecture is a requirement for calmodulin signaling to Ca _V 1.3 channels

Bilobal architecture is a requirement for calmodulin signaling to Ca _V 1.3 channels

Human Calmodulin Methyltransferase: Expression, Activity on Calmodulin, and Hsp90 Dependence

Targeting the Calmodulin-Regulated ErbB/Grb7 Signaling Axis in Cancer Therapy

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Significance of Calcium Binding, Tyrosine Phosphorylation, and Lysine Trimethylation for the Essential Function of Calmodulin in Vertebrate Cells Analyzed in a Novel Gene Replacement System

Cited by 18 publications

References 43 publications

Bilobal architecture is a requirement for calmodulin signaling to Ca V 1.3 channels

Bilobal architecture is a requirement for calmodulin signaling to Ca V 1.3 channels

Human Calmodulin Methyltransferase: Expression, Activity on Calmodulin, and Hsp90 Dependence

Targeting the Calmodulin-Regulated ErbB/Grb7 Signaling Axis in Cancer Therapy

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Bilobal architecture is a requirement for calmodulin signaling to Ca _V 1.3 channels

Bilobal architecture is a requirement for calmodulin signaling to Ca _V 1.3 channels