Role of Ca2+ activation and bilobal structure of calmodulin in nuclear and nucleolar localization

Thorogate, Richard; Török, Katalin

doi:10.1042/bj20061111

Cited by 13 publications

(9 citation statements)

References 39 publications

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“…The nucleolar localization of a handful of CaMBPs from other organisms such as calcineurin, CaM kinase II, and myosin light chain kinase suggest a role for CaM in the nucleolus (Guerriero et al 1981;Ohta et al 1990;Torgan and Daniels 2006). Fittingly, CaM has also been shown to bind and localize to mammalian nucleoli (Thorogate and Torok 2007;Wong et al 1991). Taken together, our results further support a potential role for CaM in the nucleolus which may be to regulate the binding of NumA1 to other proteins such as CBP4a (Myre and O'Day 2004a).…”

Section: Discussionsupporting

confidence: 60%

Nucleolar localization and identification of nuclear/nucleolar localization signals of the calmodulin-binding protein nucleomorphin during growth and mitosis in Dictyostelium

Catalano

O’Day

2011

Histochem Cell Biol

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The calmodulin-binding protein nucleomorphin isoform NumA1 is a nuclear number regulator in Dictyostelium that localizes to intra-nuclear patches adjacent to the nuclear envelope and to a lesser extent the nucleoplasm. Earlier studies have shown similar patches to be nucleoli but only three nucleolar proteins have been identified in Dictyostelium. Here, actinomycin-D treatment caused the loss of NumA1 localization, while calcium and calmodulin antagonists had no effect. In keeping with a nucleolar function, NumA1 moved out of the presumptive nucleoli during mitosis redistributing to areas within the nucleus, the spindle fibers, and centrosomal region before re-accumulating in the presumptive nucleoli at telophase. Together, these data verify NumA1 as a true nucleolar protein. Prior to this study, the dynamics of specific nucleolar proteins had not been determined during mitosis in Dictyostelium. FITC-conjugated peptides equivalent to presumptive nuclear localization signals within NumA1 localized to nucleoli indicating that they also act as nucleolar localization signals. To our knowledge, these represent the first precisely defined nucleolar localization signals as well as the first nuclear/nucleolar localization signals identified in Dictyostelium. Together, these results reveal that NumA1 is a true nucleolar protein and the only nucleolar calmodulin-binding protein identified in Dictyostelium. The possible use of nuclear/nucleolar localization signal-mediated drug targeting to nucleoli is discussed.

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Section: Discussionsupporting

confidence: 60%

Nucleolar localization and identification of nuclear/nucleolar localization signals of the calmodulin-binding protein nucleomorphin during growth and mitosis in Dictyostelium

Catalano

O’Day

2011

Histochem Cell Biol

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“…Although translocation of calmodulin from the cytosol into the nucleus has been observed in numerous cell types following elevation of cytosolic Ca 2+ (Mermelstein et al, 2001;Thorogate and Torok, 2004;Wu and Bers, 2007), the mechanism by which calmodulin enters the nucleus is not clear. Calmodulin does not contain an obvious motif for nuclear localisation, and might therefore 'piggyback' on other proteins that are translocated into the nucleus (Thorogate and Torok, 2007).…”

Section: Journal Of Cell Science 122 (14)mentioning

confidence: 99%

An update on nuclear calcium signalling

Bootman

Fearnley

Smyrnias

et al. 2009

Journal of Cell Science

186

194

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Over the past 15 years or so, numerous studies have sought to characterise how nuclear calcium (Ca 2+ ) signals are generated and reversed, and to understand how events that occur in the nucleoplasm influence cellular Ca 2+ activity, and vice versa. In this Commentary, we describe mechanisms of nuclear Ca 2+ signalling and discuss what is known about the origin and physiological significance of nuclear Ca 2+ transients. In particular, we focus on the idea that the nucleus has an autonomous Ca 2+ signalling system that can generate its own Ca 2+ transients that modulate processes such as gene transcription. We also discuss the role of nuclear pores and the nuclear envelope in controlling ion flux into the nucleoplasm. Journal of Cell Science 2338(which would cause its nuclear export) and through a physical interaction that occludes a nuclear-export sequence (NES) in the NFAT protein.An example of a nuclear-localised transcription factor that is regulated by both nuclear and cytosolic Ca 2+ signals is cyclic AMP response element-binding protein (CREB). The signalling mechanisms that underlie CREB activation have been worked out particularly well in neurons, in which it has been established that depolarisation leads to the rapid phosphorylation of CREB on Ser133 by Ca 2+ -calmodulin-dependent kinase IV, which provides a necessary, but not sufficient, signal for CREB-mediated gene transcription (Dolmetsch et al., 2001). The triggering event is an increase in cytosolic Ca 2+ levels in the immediate vicinity of L-type Ca 2+ channels or N-methyl-D-aspartate receptors that are found in the synapse, at a site that is distal to the nucleus (Shaywitz and Greenberg, 1999). As CREB is only found in the nucleus, the phosphorylation of Ser133 is mediated by one of several Ca 2+ -sensitive signal transduction cascades that convey information from the remote synapses into the nucleus. In the nucleus, phosphorylated CREB binds additional proteins to form a transcriptionally active complex (Shaywitz and Greenberg, 1999). Although the synaptic Ca 2+ signal does not need to propagate to the nucleus to induce phosphorylation of Ser133 on CREB, an increase in the level of nuclear Ca 2+ is required for CREB-mediated gene transcription to occur. This is because additional Ca 2+ -dependent phosphorylation of CREB and its co-activators is required (Chawla et al., 1998;Kornhauser et al., 2002). Indeed, nuclear injection of an artificial Ca 2+ buffer prevents CREB-mediated gene transcription, but not transcription induced by the serum-response element, which is sensitive to cytosolic Ca 2+ buffering (Hardingham et al., 1997).Another well-known target of nuclear Ca 2+ signalling is the transcriptional regulator downstream regulatory element antagonist modulator (DREAM). It is well established that DREAM represses the expression of prodynorphin, an opiate-receptor precursor, and that mice that lack DREAM have a constitutive analgesic condition (Cheng et al., 2002). DREAM contains four Ca 2+ -binding EF hands (a widely expressed structural mo...

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“…Evidence for a direct role for CaM in SK1 translocation, however, has not been described. Furthermore, CaM predominantly moves from the cytoplasm to the nucleus, not the plasma membrane, in response to cellular Ca 2ϩ fluxes (14,15) raising doubts over the role of CaM in SK1 localization. Thus, the actual molecular mechanism mediating translocation of SK1 to the plasma membrane has remained unresolved.…”

mentioning

confidence: 99%

Translocation of Sphingosine Kinase 1 to the Plasma Membrane Is Mediated by Calcium- and Integrin-binding Protein 1

Jarman

Moretti

Zebol

et al. 2010

Journal of Biological Chemistry

127

158

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SK1 (sphingosine kinase 1) plays an important role in many aspects of cellular regulation. Most notably, elevated cellular SK1 activity leads to increased cell proliferation, protection from apoptosis, and induction of neoplastic transformation. We have previously shown that translocation of SK1 from the cytoplasm to the plasma membrane is integral for oncogenesis mediated by this enzyme. The molecular mechanism mediating this translocation of SK1 has remained undefined. Here, we demonstrate a direct role for CIB1 (calcium and integrin-binding protein 1) in this process. We show that CIB1 interacts with SK1 in a Ca 2؉ -dependent manner at the previously identified "calmodulin-binding site" of SK1. We also demonstrate that CIB1 functions as a Ca 2؉ -myristoyl switch, providing a mechanism whereby it translocates SK1 to the plasma membrane. Both small interfering RNA knockdown of CIB1 and the use of a dominant-negative CIB1 we have generated prevent the agonist-dependent translocation of SK1. Furthermore, we demonstrate the requirement of CIB1-mediated translocation of SK1 in controlling cellular sphingosine 1-phosphate generation and associated anti-apoptotic signaling. SK1 (sphingosine kinase 1) catalyzes the formation of sphingosine 1-phosphate (S1P), 2 a bioactive phospholipid that mediates a wide variety of cellular processes. Elevated cellular S1P has been shown to be pro-proliferative and anti-apoptotic (1), and considerable evidence now exists implicating SK1 in cancer. In particular, overexpression of SK1 in NIH3T3 fibroblasts leads to a transformed phenotype and the ability to form tumors in mice, with SK1 activity also involved in oncogenic H-Ras-mediated transformation (2). Furthermore, suppression of cellular SK1 activity by genetic or pharmacologic approaches has been shown to significantly reduce tumor growth in vivo in mice (3-5) and also sensitize tumor cells to other chemotherapeutics (6).We have previously shown that although SK1 has intrinsic catalytic activity (7), its further activation is required for oncogenic signaling (8). This activation, brought about through phosphorylation at Ser-225 by ERK1/2, not only increases the catalytic activity of SK1 but also results in its translocation from the cytoplasm to the plasma membrane (9), which is essential for the oncogenic signaling by this enzyme (8, 10).Although critical in understanding SK1-induced oncogenesis, the mechanisms regulating agonist-induced translocation of SK1 to the plasma membrane are poorly understood. Studies have suggested that SK1 associates with phosphatidylserine in a phosphorylation-dependent manner, providing a possible mechanism for retention of SK1 at the plasma membrane (11). Although this may facilitate retention of SK1 at the plasma membrane, the molecular mechanism mediating the initial rapid agonist-induced translocation of SK1 has not yet been established. Calmodulin (CaM) has been indirectly implicated in this process because W7, a CaM inhibitor, blocked SK1 translocation (12), as did mutation of the CaM-bindin...

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Role of Ca2+ activation and bilobal structure of calmodulin in nuclear and nucleolar localization

Cited by 13 publications

References 39 publications

Nucleolar localization and identification of nuclear/nucleolar localization signals of the calmodulin-binding protein nucleomorphin during growth and mitosis in Dictyostelium

Nucleolar localization and identification of nuclear/nucleolar localization signals of the calmodulin-binding protein nucleomorphin during growth and mitosis in Dictyostelium

An update on nuclear calcium signalling

Translocation of Sphingosine Kinase 1 to the Plasma Membrane Is Mediated by Calcium- and Integrin-binding Protein 1

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