NFAT functions as a working memory of Ca2+ signals in decoding Ca2+ oscillation

Tomida, Taichiro

doi:10.1093/emboj/cdg381

Cited by 233 publications

(251 citation statements)

References 29 publications

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“…We note that calcium sensors are often highly sensitive to the pattern of calcium concentration changes in the cytosol; rapid calcium oscillations are seen to activate NF-kB, NFAT and Oct/OAP, while only NFAT responds to slower oscillations. 122,123 Could calcium sensors that affect actin dynamics and cellular contractility be similarly sensitive to patterns of intracellular calcium concentration changes? Clearly dissecting the role of calcium influxes in epithelial scattering will prove complex if such is the case.…”

Section: Discussionmentioning

confidence: 99%

Control of cell mechanics by RhoA and calcium fluxes during epithelial scattering

2016

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Epithelial tissues use adherens junctions to maintain tight interactions and coordinate cellular activities. Adherens junctions are remodeled during epithelial morphogenesis, including instances of epithelialmesenchymal transition, or EMT, wherein individual cells detach from the tissue and migrate as individual cells. EMT has been recapitulated by growth factor induction of epithelial scattering in cell culture. In culture systems, cells undergo a highly reproducible series of cell morphology changes, most notably cell spreading followed by cellular compaction and cell migration. These morphology changes are accompanied by striking actin rearrangements. The current evidence suggests that global changes in actomyosin-based cellular contractility, first a loss of contractility during spreading and its activation during cell compaction, are the main drivers of epithelial scattering. In this review, we focus on how spreading and contractility might be controlled during epithelial scattering. While we propose a central role for RhoA, which is well known to control cellular contractility in multiple systems and whose role in epithelial scattering is well accepted, we suggest potential roles for additional cellular systems whose role in epithelial cell biology has been less well documented. In particular, we propose critical roles for vesicle recycling, calcium channels, and calcium-dependent kinases.

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Section: Discussionmentioning

confidence: 99%

Control of cell mechanics by RhoA and calcium fluxes during epithelial scattering

2016

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“…Provocatively, altered NFAT function in mice through genetic ablation gives rise to valvulogenesis defects (23,24) that bear some similarity to the congenital heart defects observed in a mouse model of Noonan syndrome (12). There is good evidence that calcineurin which activates NFAT by dephosphorylation is regulated not just by increases in intracellular Ca 2ϩ but also by the oscillatory frequency of Ca 2ϩ (27). After NFAT translocation to the nucleus, it also has been shown that NFAT transcriptional activity is modulated by the frequency of intracellular Ca 2ϩ oscillations (17,18).…”

Section: Discussionmentioning

confidence: 99%

Gain-of-function/Noonan syndrome SHP-2/ Ptpn11 mutants enhance calcium oscillations and impair NFAT signaling

Uhlén

Burch

Zito

et al. 2006

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

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Gain-of-function mutations in SHP-2͞PTPN11 cause Noonan syndrome, a human developmental disorder. Noonan syndrome is characterized by proportionate short stature, facial dysmorphia, increased risk of leukemia, and congenital heart defects in Ϸ50% of cases. Congenital heart abnormalities are common in Noonan syndrome, but the signaling pathway(s) linking gain-of-function SHP-2 mutants to heart disease is unclear. Diverse cell types coordinate cardiac morphogenesis, which is regulated by calcium (Ca 2؉ ) and the nuclear factor of activated T-cells (NFAT). It has been shown that the frequency of Ca 2؉ oscillations regulates NFAT activity. Here, we show that in fibroblasts, Ca 2؉ oscillations in response to FGF-2 require the phosphatase activity of SHP-2. Conversely, gain-of-function mutants of SHP-2 enhanced FGF-2-mediated Ca 2؉ oscillations in fibroblasts and spontaneous Ca 2؉ oscillations in cardiomyocytes. The enhanced frequency of cardiomyocyte Ca 2؉ oscillations induced by a gain-of-function SHP-2 mutant correlated with reduced nuclear translocation and transcriptional activity of NFAT. These data imply that gain-of-function SHP-2 mutants disrupt the Ca 2؉ oscillatory control of NFAT, suggesting a potential mechanism for congenital heart defects in Noonan syndrome.calcium signaling ͉ cardiomyocytes ͉ FGF ͉ receptor tyrosine kinase signaling ͉ tyrosine phosphatases T he ubiquitously expressed src homology 2 (SH2)-containing protein tyrosine phosphatase (PTP), SHP-2 (PTPN11), regulates numerous intracellular signaling cascades that control cell proliferation, differentiation, cell survival, migration, adhesion, and apoptosis (1). SHP-2 contains two NH 2 terminus SH2 domains, a PTP domain, and a COOH terminus containing two tyrosyl phosphorylation sites (1). It is now well established that SHP-2 is required for activation of the extracellular-regulated kinases (ERKs) 1 and 2 in response to the activation of receptor tyrosine kinase (RTK) and cytokine receptors (1). The SH2 domains of SHP-2 mediate not only binding to RTKs but also scaffold proteins such as Gab-1, IRS-1, and FRS-2 (1). In virtually all cases, stimulation of SHP-2 catalysis is required for downstream signaling. The SH2 domains of SHP-2 also regulate its activation. Engagement of the NH 2 SH2 domain of SHP-2 with its cognate phosphotyrosyl protein results in its activation. The mechanism of this activation involves displacement of the NH 2 SH2 domain from the PTP domain which in the basal (unbound SH2 domain) state occludes the PTP active site. Upon NH 2 SH2 domain binding, a conformational relief of this inhibitory state is achieved and the phosphatase becomes active. Insights from the crystallographic structure of SHP-2 (2) resulted in the generation of engineered mutations at residues critical for the maintenance of the basal inactivated state of SHP-2. These mutations, within the NH 2

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“…We recorded Ca 2ϩ sparklets, [Ca 2ϩ ] i , and nuclear NFATc3 translocation in primary cultured human aortic smooth muscle cells expressing NFATc3 tagged with EGFP (17,18) (Fig. 5).…”

Section: Pkc-induced Local Ca 2؉ Signals Via Ltccs Activate Nfatc3 Anmentioning

confidence: 99%

The control of Ca ²⁺ influx and NFATc3 signaling in arterial smooth muscle during hypertension

Nieves‐Cintrón

Amberg

Navedo

et al. 2008

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

127

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Many excitable cells express L-type Ca 2؉ channels (LTCCs), which participate in physiological and pathophysiological processes ranging from memory, secretion, and contraction to epilepsy, heart failure, and hypertension. Clusters of LTCCs can operate in a PKC␣-dependent, high open probability mode that generates sites of sustained Ca 2؉ influx called ''persistent Ca 2؉ sparklets.'' Although increased LTCC activity is necessary for the development of vascular dysfunction during hypertension, the mechanisms leading to increased LTCC function are unclear. Here, we tested the hypothesis that increased PKC␣ and persistent Ca 2؉ sparklet activity contributes to arterial dysfunction during hypertension. We found that PKC␣ and persistent Ca 2؉ sparklet activity is indeed increased in arterial myocytes during hypertension. Furthermore, in human arterial myocytes, PKC␣-dependent persistent Ca 2؉ sparklets activated the prohypertensive calcineurin/NFATc3 signaling cascade. These events culminated in three hallmark signs of hypertensionassociated vascular dysfunction: increased Ca 2؉ entry, elevated arterial [Ca 2؉ ]i, and enhanced myogenic tone. Consistent with these observations, we show that PKC␣ ablation is protective against the development of angiotensin II-induced hypertension. These data support a model in which persistent Ca 2؉ sparklets, PKC␣, and calcineurin form a subcellular signaling triad controlling NFATc3-dependent gene expression, arterial function, and blood pressure. Because of the ubiquity of these proteins, this model may represent a general signaling pathway controlling gene expression and cellular function.angiotensin II ͉ myogenic tone ͉ sparklets ͉ transcription factors ͉ voltage-gated calcium channels A rterial tone is elevated during hypertension, increasing the probability of stroke, coronary artery disease, cardiac hypertrophy, and renal failure (1, 2). Although the etiology of arterial dysfunction during hypertension is unclear, multiple studies suggest that increased L-type Ca 2ϩ channel (LTCC) activity in arterial smooth muscle is a major contributor to this pathological change (3, 4). However, the mechanisms and functional implications of increased Ca 2ϩ influx via LTCCs remain unclear.In normotensive arterial smooth muscle, the opening of LTCCs produces local elevations in [Ca 2ϩ ] i called ''Ca 2ϩ sparklets'' (5, 6). Two modes of Ca 2ϩ sparklet activity have been identified (6-8). Low-activity Ca 2ϩ sparklets are produced by brief random openings of LTCCs that result in limited Ca 2ϩ influx. In contrast, long openings of LTCCs associated with PKC␣ produce high activity, persistent Ca 2ϩ sparklets that create regions of sustained Ca 2ϩ influx. Low-and high-activity, persistent Ca 2ϩ sparklets are produced by the opening of a single or a small cluster of LTCCs. PKC␣ is required for persistent, but not for low-activity, Ca 2ϩ sparklets. Under physiological conditions, Ca 2ϩ entry and global [Ca 2ϩ ] i and, thus, contraction are regulated by low-activity and PKC␣-dependent persistent Ca 2ϩ...

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NFAT functions as a working memory of Ca2+ signals in decoding Ca2+ oscillation

Cited by 233 publications

References 29 publications

Control of cell mechanics by RhoA and calcium fluxes during epithelial scattering

Control of cell mechanics by RhoA and calcium fluxes during epithelial scattering

Gain-of-function/Noonan syndrome SHP-2/ Ptpn11 mutants enhance calcium oscillations and impair NFAT signaling

The control of Ca ²⁺ influx and NFATc3 signaling in arterial smooth muscle during hypertension

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NFAT functions as a working memory of Ca2+ signals in decoding Ca2+ oscillation

Cited by 233 publications

References 29 publications

Control of cell mechanics by RhoA and calcium fluxes during epithelial scattering

Control of cell mechanics by RhoA and calcium fluxes during epithelial scattering

Gain-of-function/Noonan syndrome SHP-2/ Ptpn11 mutants enhance calcium oscillations and impair NFAT signaling

The control of Ca 2+ influx and NFATc3 signaling in arterial smooth muscle during hypertension

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The control of Ca ²⁺ influx and NFATc3 signaling in arterial smooth muscle during hypertension