Skeletal Muscle CaMKII Enriches in Nuclei and Phosphorylates Myogenic Factor SRF at Multiple Sites

Flück, Martin; Booth, Frank W.; Waxham, M. Neal

doi:10.1006/bbrc.2000.2457

Cited by 54 publications

(51 citation statements)

References 27 publications

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“…CaMKII has been shown to positively mediate the activation of the DNA-binding protein SRF in vitro by phosphorylating SRF on S103 (26). Conversely, in skeletal muscle, CaMKII has been reported to phosphorylate SRF on T160 within the MADS box (DNA-binding domain) (12) and thus negatively affect DNA binding. Given the results of the present study, it would appear that the function of specific CaMKII isozymes in regulating VSMC gene transcription merits investigation.…”

Section: Discussionmentioning

confidence: 99%

Calcium/calmodulin-dependent protein kinase II-δ isoform regulation of vascular smooth muscle cell proliferation

House¹,

Ginnan²,

Armstrong³

et al. 2007

American Journal of Physiology-Cell Physiology

107

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Section: Discussionmentioning

confidence: 99%

Calcium/calmodulin-dependent protein kinase II-δ isoform regulation of vascular smooth muscle cell proliferation

House¹,

Ginnan²,

Armstrong³

et al. 2007

American Journal of Physiology-Cell Physiology

107

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“…Serum response factor is pivotal for the regulation of the immediate-early gene c-fos and is phosphorylated in vivo on serine residue 103, which increases its DNA binding activity. Several protein kinases have been implicated in serine 103 phosphorylation, including casein kinase II, the growth factor-inducible kinase p90 rsk , Ca 2ϩ /calmodulin-dependent protein kinase II, and MK2 (8,(35)(36)(37). However, hitherto it has not been demonstrated that phosphorylation of serine 103 has any impact on transcription mediated by the serum response factor.…”

Section: Discussionmentioning

confidence: 99%

Cell Type-specific Inhibition of the ETS Transcription Factor ER81 by Mitogen-activated Protein Kinase-activated Protein Kinase 2

Janknecht

2001

Journal of Biological Chemistry

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Mitogen-activated protein kinase-activated protein kinase 2 (MK2) is an important intracellular mediator of stress signals. In this report, a novel target of MK2 has been identified, the ETS transcription factor family member ER81, whose dysregulation contributes to tumorigenesis and whose normal function is required during development. MK2 phosphorylates ER81 in vitro within its central inhibitory domain, and overexpression of MK2 leads to increased in vivo phosphorylation of ER81. Two serine residues, ER81 amino acids 191 and 216, were identified as MK2 phosphorylation sites. MK2 suppresses basal ER81-dependent transcription, and this suppressive effect is alleviated upon mutation of the MK2 phosphorylation sites in a cell type-specific manner. However, MK2 can also interfere with ER81-mediated transcription independently of serine 191 and serine 216 phosphorylation. Furthermore, MK2 overexpression counteracts the stimulation of ER81 activity by p38 mitogen-activated protein kinase. Altogether, MK2 may regulate ER81 transcriptional activity in a cell type-specific manner and thereby modulate various physiological processes beyond stress responses.Three mitogen-activated protein (MAP) 1 kinase classes exist in the mammalian cell, the growth factor-activated ERK-MAP kinases and two stress-activated protein kinase families, JNK and p38 (1). A plethora of stimuli, including serum, growth factors, cytokines, tumor necrosis factor-␣, UV light, hyperosmolarity, and heat, trigger intracellular signal transduction pathways that lead to the activation of one or more of these MAP kinase classes. Upon activation, MAP kinases functionally regulate many proteins through serine/threonine phosphorylation, including distinct MAPKAP kinases, which in turn phosphorylate and modulate downstream effectors.In particular, MAPKAP kinase 2 (MK2) is stimulated by signals such as heat shock and tumor necrosis factor-␣ via the p38-MAP kinase pathway (2, 3). On the other hand, lack of MK2 activity severely dampens tumor necrosis factor-␣ biosynthesis, causing resistance to lipopolysaccharide-induced endotoxic shock (4). Furthermore, 5-lipoxygenase, which catalyzes important steps in the synthesis of a group of inflammatory mediators, leukotrienes, is a downstream target of MK2 (5), suggesting that MK2 may affect the inflammatory response at different levels.A variety of other proteins are phosphorylated by MK2, implicating the involvement of MK2 in many different physiological processes dependent on these target proteins. Among those are the small heat shock proteins (6), the F-actin-binding lymphocyte-specific protein 1 (7), serum response factor that is involved in the regulation of the c-fos proto-oncogene (8), and the transcription factor CREB, which can be phosphorylated by MK2 upon fibroblast or nerve growth factor stimulation (9, 10).ER81 is a transcription factor of the ETS protein superfamily that is characterized by a highly conserved DNA binding domain (11). Gene regulation mediated by ER81 is dependent on its N-and C-termina...

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“…7). Such a site exists in the DNA binding region of the MADS box of SRF (Thr160) and has been shown to be phosphorylated in a myogenic system by calmodulin kinase II (CaMKII) (11). Although other S/T-F sites exist in SRF, the primary sequence surrounding T160 has the closest consensus to a PKC␦ substrate (34).…”

Section: Vol 24 2004 Pkc␦ Inhibits Srf Binding In Senescent Fibroblmentioning

confidence: 99%

Protein Kinase Cδ Blocks Immediate-Early Gene Expression in Senescent Cells by Inactivating Serum Response Factor

Wheaton

Riabowol

2004

Molecular and Cellular Biology

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Fibroblasts lose the ability to replicate in response to growth factors and become unable to express growth-associated immediate-early genes, including c-fos and egr-1, as they become senescent. The serum response factor (SRF), a major transcriptional activator of immediate-early gene promoters, loses the ability to bind to the serum response element (SRE) and becomes hyperphosphorylated in senescent cells. We identify protein kinase C delta (PKC␦) as the kinase responsible for inactivation of SRF both in vitro and endogenously in senescent cells. This is due to a higher level of PKC␦ activity as cells age, production of the PKC␦ catalytic fragment, and its nuclear localization in senescent but not in low-passage-number cells. The phosphorylation of T160 of SRF by PKC␦ in vitro and in vivo led to loss of SRF DNA binding activity. Both the PKC␦ inhibitor rottlerin and ectopic expression of a dominant negative form of PKC␦ independently restored SRE-dependent transcription and immediate-early gene expression in senescent cells. Modulation of PKC␦ activity in vivo with rottlerin or bistratene A altered senescent-and young-cell morphology, respectively. These observations support the idea that the coordinate transcriptional inhibition of several growth-associated genes by PKC␦ contributes to the senescent phenotype.

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Skeletal Muscle CaMKII Enriches in Nuclei and Phosphorylates Myogenic Factor SRF at Multiple Sites

Cited by 54 publications

References 27 publications

Calcium/calmodulin-dependent protein kinase II-δ isoform regulation of vascular smooth muscle cell proliferation

Calcium/calmodulin-dependent protein kinase II-δ isoform regulation of vascular smooth muscle cell proliferation

Cell Type-specific Inhibition of the ETS Transcription Factor ER81 by Mitogen-activated Protein Kinase-activated Protein Kinase 2

Protein Kinase Cδ Blocks Immediate-Early Gene Expression in Senescent Cells by Inactivating Serum Response Factor

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