The Interaction of Calmodulin with Novel Target Proteins

Chun, Kelly Y.; Sacks, David B.

doi:10.1007/978-94-010-0688-0_32

Cited by 5 publications

(5 citation statements)

References 94 publications

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“…For example, E‐cadherin is frequently downregulated in invasive tumours and is believed to be a tumour suppressor (Bracke et al ., 1996). β‐catenin and calmodulin, both of which stimulate cell proliferation, are upregulated in several malignant tumour types (Chun & Sacks, 2000; Polakis, 1999). Rho GTPases are important components of epithelial cell transformation and can promote tumour metastasis by increasing cell motility and migration (Ridley, 2001; Sahai & Marshall, 2002).…”

Section: Introductionmentioning

confidence: 99%

IQGAP proteins are integral components of cytoskeletal regulation

2003

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IQGAP1 is a scaffolding protein that binds to a diverse array of signalling and structural molecules. By interacting with its target proteins, human IQGAP1 participates in multiple cellular functions, including Ca 2+ /calmodulin signalling, cytoskeletal architecture, CDC42 and Rac signalling, E-cadherin-mediated cell-cell adhesion and β-catenin-mediated transcription. Yeast IQGAP homologues are important regulators of cellular morphogenesis because they are required for budding and cytokinesis. Here we discuss the structure and function of IQGAP1 as a member of the family of IQGAP proteins and summarize the current knowledge about IQGAP1 and IQGAP2. Collectively, these data reveal that IQGAP1 is a fundamental regulator of cytoskeletal function.

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Section: Introductionmentioning

confidence: 99%

IQGAP proteins are integral components of cytoskeletal regulation

2003

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“…Calmodulin is a multifunctional signaling protein that elicits myriad effects in cells by modulating the function of target proteins (1)(2)(3). A diverse array of proteins are regulated by Ca 2ϩ /calmodulin, ranging from the classic kinases (such as myosin light chain kinase and the Ca 2ϩ /calmodulin kinase family) (1) to ion channels and anthrax (4,5).…”

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confidence: 99%

Elucidation of the Interaction of Calmodulin with the IQ Motifs of IQGAP1

Sacks

2003

Journal of Biological Chemistry

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110

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Calmodulin regulates the function of numerous proteins by binding to short regions on the target molecule. IQ motifs, which are found in over 100 human proteins, appear in tandem repeats and bind calmodulin in the absence of Ca 2؉ . One of these IQ-containing proteins, IQGAP1, interacts with several targets, including Cdc42, ␤-catenin, E-cadherin, and actin, in a calmodulin-regulated manner. To elucidate the molecular mechanism by which apocalmodulin and Ca 2؉ /calmodulin differentially regulate IQGAP1, a series of constructs of IQGAP1 with selected point mutations of the four tandem IQ motifs were generated. Mutating the basic charged arginine residues in all four IQ motifs abrogated binding of IQGAP1 to apocalmodulin, but had no effect on its interaction with Ca 2؉ /calmodulin. Analysis of IQGAP1 constructs with point mutations in single, double, or triple IQ motifs revealed that apocalmodulin bound only to IQ3 and IQ4. By contrast to the arginine mutant constructs, mutation of selected hydrophobic residues in the IQ motifs produced an IQGAP1 protein incapable of binding either apocalmodulin or Ca 2؉ /calmodulin. These results, which differ from the conventional model of Ca 2؉ -independent binding of calmodulin to IQ motifs, provide insight into the complexity of the molecular interactions between calmodulin and IQ motifs.

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“…Conversely, other proteins can alter the state of ER independent of ligand binding. For example, phosphorylation of ER by several protein kinases, including a calmodulin-stimulated kinase, modulates ER transcriptional activation (5).Calmodulin, a ubiquitous modulator of Ca 2ϩ signaling (6), regulates the function of multiple, diverse proteins (7,8). A substantial body of evidence supports a role for Ca 2ϩ and calmodulin in estrogen action (Ref.…”

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confidence: 99%

“…Calmodulin, a ubiquitous modulator of Ca 2ϩ signaling (6), regulates the function of multiple, diverse proteins (7,8). A substantial body of evidence supports a role for Ca 2ϩ and calmodulin in estrogen action (Ref.…”

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confidence: 99%

Calmodulin Regulates the Transcriptional Activity of Estrogen Receptors

Sacks

2003

Journal of Biological Chemistry

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The steroid hormone estrogen elicits biological effects in cells by binding to and activating the estrogen receptor (ER). Estrogen binding induces a conformational change in the receptor, inducing nuclear translocation and transcriptional activation of ER. The ubiquitous Ca 2؉ -binding protein calmodulin has been shown to interact directly with ER and enhance its stability. To further elucidate the functional sequelae of the association between calmodulin and ER, we examined the effect on ER transcriptional activation of specifically inhibiting calmodulin. The cell-permeable calmodulin antagonist CGS9343B prevented estrogen-induced transcriptional activation by ER, without altering basal transcription. The inhibition was dose-dependent and independent of the time of estrogen stimulation. To validate these findings, calmodulin function was also neutralized by targeted expression of a specific inhibitor peptide. By inserting localization signals, the inhibitor peptide was selectively targeted to different subcellular domains. Inactivation of calmodulin function in the nucleus virtually eliminated estrogen-stimulated ER transcriptional activation. By contrast, when membrane calmodulin was specifically neutralized, estrogen-stimulated transcriptional activation by ER was only slightly attenuated. Importantly, the inhibitor peptides did not significantly reduce the amount of ER in the cells. Together, these data demonstrate that calmodulin is a fundamental component of ER transcriptional activation.The classic steroid hormone estrogen promotes the proliferation of both normal and malignant breast epithelial cells and shortens the cell cycle. Estrogen mediates its biological effects in cells through the estrogen receptor (ER), 1 a member of the nuclear receptor family of ligand-dependent transcription factors (reviewed in Refs. 1 and 2). Analogous to other steroid hormone receptors, ER is an intracellular transcription factor composed of six domains. Estrogen binding to the C-terminal hormone-binding domain induces conformational changes in ER, thereby promoting its dimerization and nuclear localization. The DNA-binding domain of the activated ER binds to DNA sequences, termed estrogen response elements, found in the regulatory regions of target genes. Several factors, including coactivators, corepressors, and integrator proteins, are important in ER-mediated transcription (reviewed in Refs. 3 and 4). It is becoming apparent that transcriptional regulation requires the recruitment by ER of multiple, distinct proteins that cooperate to achieve the required response (3). These factors can alter the magnitude of cellular responses to estrogen.There are yet additional factors that modulate ER function. For example, ER interacts with members of the heat-shock protein family (1), and dissociation of heat-shock protein seems to be necessary for ER to activate transcription. One of the major roles of ligand binding is to change the nature of proteinprotein interactions between steroid receptors and other proteins (2). Convers...

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The Interaction of Calmodulin with Novel Target Proteins

Cited by 5 publications

References 94 publications

IQGAP proteins are integral components of cytoskeletal regulation

IQGAP proteins are integral components of cytoskeletal regulation

Elucidation of the Interaction of Calmodulin with the IQ Motifs of IQGAP1

Calmodulin Regulates the Transcriptional Activity of Estrogen Receptors

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