Identification of the Anti-proliferative Protein Tob as a MAPK Substrate

Maekawa, Momoko; Nishida, Eisuke; Tanoue, Takuji

doi:10.1074/jbc.m204506200

Cited by 68 publications

(65 citation statements)

References 30 publications

(24 reference statements)

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“…ERK2 is known to interact with substrates, activators, and scaffold proteins through the D domain and the DEF domain (28,29,32,37,38). Vinexin contains both a putative D domain and DEF domain (FPFP sequence), like other physiological substrates, including Elk-1 and Tob (28,39). We demonstrated here that the RRAA mutant, which has mutations in the putative D domain, still interacted with ERK2 (Fig.…”

Section: Discussionmentioning

confidence: 65%

Extracellular Signal-regulated Kinase Activated by Epidermal Growth Factor and Cell Adhesion Interacts with and Phosphorylates Vinexin

Mitsushima

Suwa

Amachi

et al. 2004

Journal of Biological Chemistry

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Extracellular signal-regulated kinase 1/2 (ERK1/2) is activated by various extracellular stimuli including growth factors and cytokines and plays a pivotal role in regulating cell proliferation and differentiation by phosphorylating nuclear transcription factors. Recently, it was reported that activated ERK1/2 also concentrates at adhesion sites and regulates cell spreading and migration. Vinexin is a focal adhesion protein regulating both cell spreading and growth factor signaling. We show here that vinexin was directly phosphorylated by ERK1/2 upon stimulation with growth factors. ERK1/2 phosphorylated the linker region of vinexin between the second and third SH3 domains. Site-directed mutagenesis revealed that ERK2 mainly phosphorylated the serine 189 residue of vinexin ␤. Furthermore, vinexin ␤ interacted with ERK1/2 both in vitro and in vivo. Vinexin interacted with the active but not inactive form of ERK1/2. A putative DEF (docking for ERK FXFP) domain located in the linker region of vinexin was required for the interaction with ERK1/2 and efficient phosphorylation of vinexin ␤ by ERK2. Finally, we showed that cell adhesion to fibronectin also induced the association of vinexin ␤ with ERK2 and the phosphorylation of vinexin ␤. Furthermore, vinexin and ERK were co-localized to the periphery of cells during cell spreading on fibronectin. Together, these results suggest that vinexin is a novel substrate of ERK2 and may play roles in ERK-dependent cell regulation during cell spreading as well as in growth factor-induced responses.Mitogen-activated protein kinase (MAPK) 1 consists of four subfamilies, extracellular signal-regulated kinase 1/2 (ERK1/ 2), c-Jun N-terminal kinase/stress-activated kinase, p38MAPK, and ERK5. ERK1/2 is mainly activated by various growth factors and regulates a diverse array of cellular events including cell proliferation, survival, and differentiation (1, 2). Many extracellular signals activate membrane receptors, including receptor tyrosine kinases, G protein-coupled receptors, or integrins, leading to the activation of Raf. Activated Raf, in turn, activates MEK (MAPK/ERK kinase) by the direct phosphorylation of dual serine residues. Activated MEK also directly phosphorylates and activates ERK1/2. Once activated, ERK1/2 enters the nucleus and phosphorylates nuclear transcription factors, including Elk-1, Sap1, c-Myc, and c-Fos (3).Recently, ERK has been shown to play crucial roles in regulating cell adhesion and cell migration independent of its nuclear functions (4 -7). ERK is involved in the migration of breast cancer cells stimulated by urokinase-type tissue plasminogen activator. Neither de novo gene transcription nor protein synthesis is required for this process (5). Activation of ERK is also suggested to be involved in the chemotaxis or the extension of pseudopodia, probably through the phosphorylation of cytoplasmic proteins (8, 9). Furthermore, ERK is well known to be activated by integrin engagement and to be localized to adhesion sites (7, 10 -14). Although some cytoplasm...

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Section: Discussionmentioning

confidence: 65%

Extracellular Signal-regulated Kinase Activated by Epidermal Growth Factor and Cell Adhesion Interacts with and Phosphorylates Vinexin

Mitsushima

Suwa

Amachi

et al. 2004

Journal of Biological Chemistry

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“…ERK1/2 have been shown to phosphorylate cytoskeletal proteins and microtubule-associated proteins, which are involved in cell migration and morphological alterations (28 -31). It has also been recently shown that some cytoplasmic proteins important in cell viability and apoptosis are regulated through their phosphorylation by ERK1/2 (32)(33)(34). A number of proteins involved in various signaling pathways are phosphorylated by ERK1/2, including phospholipase A 2 (35), some components of the ERK cascade itself, such as Raf-1 (36) and MEK1 (37), phosphodiesterase 4D (38), GRK2 (39), ␤-arrestin1 (40), and others.…”

Section: Discussionmentioning

confidence: 99%

Differential Kinetic and Spatial Patterns of β-Arrestin and G Protein-mediated ERK Activation by the Angiotensin II Receptor

Ahn

Shenoy

Wei

et al. 2004

Journal of Biological Chemistry

467

412

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The seven-membrane-spanning angiotensin II type 1A receptor activates the mitogen-activated protein kinases extracellular signal-regulated kinases 1 and 2 (ERK1/2) by distinct pathways dependent on either G protein (likely G q /G 11 ) or ␤-arrestin2. Here we sought to distinguish the kinetic and spatial patterns that characterize ERK1/2 activated by these two mechanisms. We utilized ␤-arrestin RNA interference, the protein kinase C inhibitor Ro-31-8425, a mutant angiotensin II receptor (DRY/AAY), and a mutant angiotensin II peptide (SIIangiotensin), which are incapable of activating G proteins, to isolate the two pathways in HEK-293 cells. G protein-dependent activation was rapid (peak <2 min), quite transient (t1 ⁄2 ϳ2 min), and led to nuclear translocation of the activated ERK1/2 as assessed by confocal microscopy. In contrast, ␤-arrestin2-dependent activation was slower (peak 5-10 min), quite persistent with little decrement noted out to 90 min, and entirely confined to the cytoplasm. Moreover, ERK1/2 activated via ␤-arrestin2 accumulated in a pool of cytoplasmic endosomal vesicles that also contained the internalized receptors and ␤-arrestin. Such differential regulation of the temporal and spatial patterns of ERK1/2 activation via these two pathways strongly implies the existence of distinct physiological endpoints.

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“…Thus, a strong correlation exists between sustained ERK1/2 activity, AP-1 protein expression and accumulation of cyclin D1 in G1 phase. ERK1/2 signaling also regulates Cyclin D1 transcription through phosphorylation and inactivation of Tob (Maekawa et al, 2002;Suzuki et al, 2002). Tob is a member of an emerging family of antiproliferative genes, which acts as a transcriptional co-repressor and negatively regulates Cyclin D1 transcription by recruiting histone deacetylase activity to the promoter (Yoshida et al, 2003).…”

Section: Erk1/2 Map Kinases In Cell Cycle Control S Meloche and J Poumentioning

confidence: 99%

The ERK1/2 mitogen-activated protein kinase pathway as a master regulator of the G1- to S-phase transition

2007

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The Ras-dependent extracellular signal-regulated kinase (ERK)1/2 mitogen-activated protein (MAP) kinase pathway plays a central role in cell proliferation control. In normal cells, sustained activation of ERK1/ERK2 is necessary for G1-to S-phase progression and is associated with induction of positive regulators of the cell cycle and inactivation of antiproliferative genes. In cells expressing activated Ras or Raf mutants, hyperactivation of the ERK1/2 pathway elicits cell cycle arrest by inducing the accumulation of cyclin-dependent kinase inhibitors. In this review, we discuss the mechanisms by which activated ERK1/ERK2 regulate growth and cell cycle progression of mammalian somatic cells. We also highlight the findings obtained from gene disruption studies.

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Identification of the Anti-proliferative Protein Tob as a MAPK Substrate

Abstract: Mitogen-activated protein kinases (MAPKs

Cited by 68 publications

References 30 publications

Extracellular Signal-regulated Kinase Activated by Epidermal Growth Factor and Cell Adhesion Interacts with and Phosphorylates Vinexin

Extracellular Signal-regulated Kinase Activated by Epidermal Growth Factor and Cell Adhesion Interacts with and Phosphorylates Vinexin

Differential Kinetic and Spatial Patterns of β-Arrestin and G Protein-mediated ERK Activation by the Angiotensin II Receptor

The ERK1/2 mitogen-activated protein kinase pathway as a master regulator of the G1- to S-phase transition

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