ERBIN is a new SARA-interacting protein: competition between SARA and SMAD2 and SMAD3 for binding to ERBIN

Sflomos, George; Kostaras, Eleftherios; Panopoulou, Ekaterini; Παππάς, Νικόλαος; Kyrkou, Athena; Politou, Anastasia S.; Fotsis, Theodore; Murphy, Carol

doi:10.1242/jcs.062307

Cited by 23 publications

(24 citation statements)

References 51 publications

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“…interact with SHOC2 and SMAD3, respectively (22,23,40). A truncation of DSG1 lacking the unique PL, RUD, and TD regions, though capable of mediating previously mapped interactions with Pg (41), failed to bind Erbin.…”

Section: Figurementioning

confidence: 90%

Desmoglein-1/Erbin interaction suppresses ERK activation to support epidermal differentiation

Harmon

Simpson²,

Johnson³

et al. 2013

J. Clin. Invest.

130

158

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Genetic disorders of the Ras/MAPK pathway, termed RASopathies, produce numerous abnormalities, including cutaneous keratodermas. The desmosomal cadherin, desmoglein-1 (DSG1), promotes keratinocyte differentiation by attenuating MAPK/ERK signaling and is linked to striate palmoplantar keratoderma (SPPK). This raises the possibility that cutaneous defects associated with SPPK and RASopathies share certain molecular faults. To identify intermediates responsible for executing the inhibition of ERK by DSG1, we conducted a yeast 2-hybrid screen. The screen revealed that Erbin (also known as ERBB2IP), a known ERK regulator, binds DSG1. Erbin silencing disrupted keratinocyte differentiation in culture, mimicking aspects of DSG1 deficiency. Furthermore, ERK inhibition and the induction of differentiation markers by DSG1 required both Erbin and DSG1 domains that participate in binding Erbin. Erbin blocks ERK signaling by interacting with and disrupting Ras-Raf scaffolds mediated by SHOC2, a protein genetically linked to the RASopathy, Noonan-like syndrome with loose anagen hair (NS/LAH). DSG1 overexpression enhanced this inhibitory function, increasing Erbin-SHOC2 interactions and decreasing Ras-SHOC2 interactions. Conversely, analysis of epidermis from DSG1-deficient patients with SPPK demonstrated increased Ras-SHOC2 colocalization and decreased Erbin-SHOC2 colocalization, offering a possible explanation for the observed epidermal defects. These findings suggest a mechanism by which DSG1 and Erbin cooperate to repress MAPK signaling and promote keratinocyte differentiation.

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Section: Figurementioning

confidence: 90%

Desmoglein-1/Erbin interaction suppresses ERK activation to support epidermal differentiation

Harmon

Simpson²,

Johnson³

et al. 2013

J. Clin. Invest.

130

158

View full text Add to dashboard Cite

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“…Like TMEPAI, its homolog C18 ORF1 can also interfere with the interaction of Smad2 and Smad3 with SARA and, thus, attenuates Smad recruitment to TβRI (Nakano et al 2014). Similarly, ERBIN (ERBB2/HER2-interacting protein), a SARA-interacting protein, inhibits TGF-β signaling by competing with SARA for the association with Smad2 and Smad3 and inhibiting their activation (Sflomos et al 2011). Although all of these studies support the role of SARA in promoting TGF-β signaling, it was reported that silencing SARA expression using small interfering RNA (siRNA) has no effect on TGF-β signaling in HeLa cells (Bakkebo et al 2012), which might be caused by incomplete down-regulation of SARA expression and/or a redundant functions of Hrs/Hgs.…”

Section: Activation Of Smads By the Receptor Complexesmentioning

confidence: 99%

TGF-β Signaling from Receptors to Smads

Hata

Chen

2016

Cold Spring Harb Perspect Biol

662

527

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Transforming growth factor β (TGF-β) and related growth factors are secreted pleiotropic factors that play critical roles in embryogenesis and adult tissue homeostasis by regulating cell proliferation, differentiation, death, and migration. The TGF-β family members signal via heteromeric complexes of type I and type II receptors, which activate members of the Smad family of signal transducers. The main attribute of the TGF-β signaling pathway is context-dependence. Depending on the concentration and type of ligand, target tissue, and developmental stage, TGF-β family members transmit distinct signals. Deregulation of TGF-β signaling contributes to developmental defects and human diseases. More than a decade of studies have revealed the framework by which TGF-βs encode a context-dependent signal, which includes various positive and negative modifiers of the principal elements of the signaling pathway, the receptors, and the Smad proteins. In this review, we first introduce some basic components of the TGF-β signaling pathways and their actions, and then discuss posttranslational modifications and modulatory partners that modify the outcome of the signaling and contribute to its context-dependence, including small noncoding RNAs.

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“…1 C). ERB IN is known to form protein scaffolds and can complex with SMAD2/3, sequestering it in the cytoplasm, thus preventing transcriptional activity in a manner similar to that seen with STAT3C overexpression in vitro (Sflomos et al, 2011;Wang et al, 2016). Using gel filtration chromatography, we identified a large molecular weight fraction containing SMAD2/3, STAT3, and ERB IN and that contained pSMAD2/3 after STAT3 activation by IL-6 ( Fig.…”

Section: Introductionmentioning

confidence: 90%