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Human ortholog of Drosophila Melted impedes SMAD2 release from TGF-? receptor I to inhibit TGF-? signaling.

ABSTRACT: Drosophila melted encodes a pleckstrin homology (PH) domain-containing protein that enables normal tissue growth, metabolism, and photoreceptor differentiation by modulating Forkhead box O (FOXO), target of rapamycin, and Hippo signaling pathways. Ventricular zone expressed PH domain-containing 1 (VEPH1) is the mammalian ortholog of melted, and although it exhibits tissue-restricted expression during mouse development and is potentially amplified in several human cancers, little is known of its function. Here we explore the impact of VEPH1 expression in ovarian cancer cells by gene-expression profiling. In cells with elevated VEPH1 expression, transcriptional programs associated with metabolism and FOXO and Hippo signaling were affected, analogous to what has been reported for Melted. We also observed altered regulation of multiple transforming growth factor-? (TGF-?) target genes. Global profiling revealed that elevated VEPH1 expression suppressed TGF-?-induced transcriptional responses. This inhibitory effect was verified on selected TGF-? target genes and by reporter gene assays in multiple cell lines. We further demonstrated that VEPH1 interacts with TGF-? receptor I (T?RI) and inhibits nuclear accumulation of activated Sma- and Mad-related protein 2 (SMAD2). We identified two T?RI-interacting regions (TIRs) with opposing effects on TGF-? signaling. TIR1, located at the N terminus, inhibits canonical TGF-? signaling and promotes SMAD2 retention at T?RI, similar to full-length VEPH1. In contrast, TIR2, located at the C-terminal region encompassing the PH domain, decreases SMAD2 retention at T?RI and enhances TGF-? signaling. Our studies indicate that VEPH1 inhibits TGF-? signaling by impeding the release of activated SMAD2 from T?RI and may modulate TGF-? signaling during development and cancer initiation or progression.

SUBMITTER: Shathasivam P

PROVIDER: S-EPMC4466715 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Human ortholog of Drosophila Melted impedes SMAD2 release from TGF-β receptor I to inhibit TGF-β signaling.

Shathasivam Premalatha P Kollara Alexandra A Ringuette Maurice J MJ Virtanen Carl C Wrana Jeffrey L JL Brown Theodore J TJ

Proceedings of the National Academy of Sciences of the United States of America 20150526 23

Drosophila melted encodes a pleckstrin homology (PH) domain-containing protein that enables normal tissue growth, metabolism, and photoreceptor differentiation by modulating Forkhead box O (FOXO), target of rapamycin, and Hippo signaling pathways. Ventricular zone expressed PH domain-containing 1 (VEPH1) is the mammalian ortholog of melted, and although it exhibits tissue-restricted expression during mouse development and is potentially amplified in several human cancers, little is known of its ...[more]

PMID: 26039994

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Project description:Regulation of transforming growth factor-beta (TGF-beta) signaling is critical in vertebrate development, as several members of the TGF-beta family have been shown to act as morphogens, controlling a variety of cell fate decisions depending on concentration. Little is known about the role of intracellular regulation of the TGF-beta pathway in development. E3 ubiquitin ligases target specific protein substrates for proteasome-mediated degradation, and several are implicated in signaling. We have shown that Arkadia, a nuclear RING-domain E3 ubiquitin ligase, is essential for a subset of Nodal functions in the embryo, but the molecular mechanism of its action in embryonic cells had not been addressed. Here, we find that Arkadia facilitates Nodal signaling broadly in the embryo, and that it is indispensable for cell fates that depend on maximum signaling. Loss of Arkadia in embryonic cells causes nuclear accumulation of phospho-Smad2/3 (P-Smad2/3), the effectors of Nodal signaling; however, these must be repressed or hypoactive as the expression of their direct target genes is reduced or lost. Molecular and functional analysis shows that Arkadia interacts with and ubiquitinates P-Smad2/3 causing their degradation, and that this is via the same domains required for enhancing their activity. Consistent with this dual function, introduction of Arkadia in homozygous null (-/-) embryonic stem cells activates the accumulated and hypoactive P-Smad2/3 at the expense of their abundance. Arkadia-/- cells, like Smad2-/- cells, cannot form foregut and prechordal plate in chimeras, confirming this functional interaction in vivo. As Arkadia overexpression never represses, and in some cells enhances signaling, the degradation of P-Smad2/3 by Arkadia cannot occur prior to their activation in the nucleus. Therefore, Arkadia provides a mechanism for signaling termination at the end of the cascade by coupling degradation of P-Smad2/3 with the activation of target gene transcription. This mechanism can account for achieving efficient and maximum Nodal signaling during embryogenesis and for rapid resetting of target gene promoters allowing cells to respond to dynamic changes in extracellular signals.

Dataset Information

Human ortholog of Drosophila Melted impedes SMAD2 release from TGF-? receptor I to inhibit TGF-? signaling.

Publications

Human ortholog of Drosophila Melted impedes SMAD2 release from TGF-β receptor I to inhibit TGF-β signaling.

Similar Datasets

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