The Focal Adhesion Protein Vinexin α Regulates the Phosphorylation and Activity of Estrogen Receptor α

Tujague, Michel; Thomsen, Jane S.; Mizuki, Kazuhito; Sadek, Christine M.; Gustafsson, Jan‐Åke

doi:10.1074/jbc.m312160200

Cited by 21 publications

(19 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Indeed, the progesterone receptor interacts with cCbl-associated protein/ponsin through a proline-rich motif in its N-terminal domain (42). The ER has also been recently reported to interact with the ␣ isoform of vinexin through its N-terminal domain (43). Based on these observations, it appears that this family of proteins, which can be present not only in the cytoplasm, but also in the nucleus, would be novel regulators of nuclear receptors.…”

Section: Discussionmentioning

confidence: 98%

Vinexin β Interacts with the Non-phosphorylated AF-1 Domain of Retinoid Receptor γ (RARγ) and Represses RARγ-mediated Transcription

Bour¹,

Plassat

Bauer

et al. 2005

Journal of Biological Chemistry

View full text Add to dashboard Cite

Nuclear retinoic acid receptors (RARs) are ligand-dependent transcription factors that regulate the expression of retinoic acid target genes. Although the importance of RAR phosphorylation in their N-terminal domain is clearly established, the underlying mechanism for the phosphorylation-dependent transcriptional activity of the receptors had not been elucidated yet. Here, using a yeast two-hybrid system, we report the isolation of vinexin ␤ as a new cofactor that interacts with the N-terminal A/B domain of the RAR␥ isotype. Vinexin ␤ is a multiple SH3 motif-containing protein associated with the cytoskeleton and also present in the nucleus. We demonstrate that vinexin ␤ colocalizes with RAR␥ in the nucleus and interacts with the non-phosphorylated form of the AF-1 domain of RAR␥. We also show that this interaction is prevented upon phosphorylation of the AF-1 domain. Using F9 cells stably overexpressing vinexin ␤ or vinexin knockdown by RNA interference, we demonstrate that vinexin ␤ is an inhibitor of RAR␥-mediated transcription. We propose a model in which phosphorylation of the AF-1 domain controls RAR␥-mediated transcription through triggering the dissociation of vinexin ␤.Retinoic acid (RA), 1 the most potent biologically active metabolite of vitamin A, influences the proliferation, differentiation, and apoptosis of a variety of cell types through modifications of expression of subsets of RA target genes (1-3). The effects of RA are mediated by two classes of nuclear receptors, the retinoic acid receptors (RAR␣, RAR␤, and RAR␥) and the retinoid X receptors (RXR␣, RXR␤, and RXR␥), which function as ligand-dependent heterodimeric RAR/RXR transcription activators (4 -6). RARs and RXRs exhibit a conserved modular structure (see Fig. 1A) with a central DNA-binding domain and two activation domains (AF-1 and AF-2) that synergize for the activation of RA target genes.Ligand-induced conformational changes in the AF-2 domain of RARs bound at cognate response elements (RA response elements) located in the promoter of target genes cause the dynamic, coordinated, and combinatorial recruitment of coactivators and large complexes with chromatin-modifying and chromatin-remodeling activity, which will decompact repressive chromatin to allow positioning of the transcription machinery at the promoter (2, 7). Other proteins are also recruited and serve as connections with the transcription machinery. In line with this, RARs interact with the general transcription factor TFIIH (8, 9). This results in the phosphorylation of one residue located in their N-terminal AF-1 domain (Ser 77 in RAR␣1, Ser 79 in RAR␥1, and Ser 68 in RAR␥2) (see Fig. 1A) by the Cdk7 subunit of TFIIH, which has cyclin H-dependent kinase activity. This phosphorylation process, which has been extensively studied especially in the case of RAR␣ (10), plays a critical role in the response to RA.However, in the particular case of the RAR␥ isotype, phosphorylation by TFIIH, although necessary, is not sufficient. Indeed, to be transcriptionally active, RAR␥ needs...

show abstract

Section: Discussionmentioning

confidence: 98%

Vinexin β Interacts with the Non-phosphorylated AF-1 Domain of Retinoid Receptor γ (RARγ) and Represses RARγ-mediated Transcription

Bour¹,

Plassat

Bauer

et al. 2005

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Under the conditions, immunoreactivity of anti-phospho-Vin was detected at focal adhesions where GFP-vinexinb accumulated (Figure 3Bd-f). Phosphorylation signal in the nucleus may be related to vinexin-dependent gene-expression control although the possibility of nonspecific signals is not ruled out (Tujague et al, 2004;Bour et al, 2005). As is the case of T24 cells, GFP-vinexinb-SA accumulated at focal adhesions with little phosphorylation signal (Figure 3Bg-k).…”

Section: Intracellular Localization Of Vinexin In Migrating and Spreamentioning

confidence: 97%

Essential roles of ERK-mediated phosphorylation of vinexin in cell spreading, migration and anchorage-independent growth

et al. 2007

View full text Add to dashboard Cite

“…Moreover, vinexin ␤ regulates the EGF-induced activation of JNK and the anchoragedependent activation of ERK2 induced by EGF (20,21). Furthermore, it was reported that vinexin interacted with scaffold attachment factor B2 or estrogen receptor, both of which are implicated in the response to steroid hormone (22,23). These observations suggested that vinexin is involved not only in the regulation of cell adhesion/cytoskeletal organization, but also in the regulation of signal transduction.…”

mentioning

confidence: 88%

“…Thus, one possibility is that vinexin links the active form of ERK to its substrates as a scaffold protein. We and others reported that vinexin bound to Sos (20) and estrogen receptor (23), both of which are phosphorylated and regulated by ERK (24,46,47), through the third SH3 domain and the N-terminal half of vinexin ␣, respectively. Vinexin bound to the active form of ERK through the linker region between the second and third SH3 domains.…”

Section: Discussionmentioning

confidence: 99%

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

View full text Add to dashboard Cite

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...

show abstract

The Focal Adhesion Protein Vinexin α Regulates the Phosphorylation and Activity of Estrogen Receptor α

Cited by 21 publications

References 58 publications

Vinexin β Interacts with the Non-phosphorylated AF-1 Domain of Retinoid Receptor γ (RARγ) and Represses RARγ-mediated Transcription

Vinexin β Interacts with the Non-phosphorylated AF-1 Domain of Retinoid Receptor γ (RARγ) and Represses RARγ-mediated Transcription

Essential roles of ERK-mediated phosphorylation of vinexin in cell spreading, migration and anchorage-independent growth

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

Contact Info

Product

Resources

About