Daple is a novel non-receptor GEF required for trimeric G protein activation in Wnt signaling

Nicolas Aznar; Krishna K Midde; Ying Dunkel; Inmaculada Lopez-Sanchez; Yelena Pavlova; Arthur Marivin; Jorge Barbazán; Fiona Murray; Ulrich Nitsche; Klaus-Peter Janssen; Karl Willert; Ajay Goel; Miguel Abal; Mikel Garcia-Marcos; Pradipta Ghosh

doi:10.7554/eLife.07091

Daple is a novel non-receptor GEF required for trimeric G protein activation in Wnt signaling

Nicolas Aznar, Krishna K Midde, Ying Dunkel, Inmaculada Lopez-Sanchez, Yelena Pavlova, Arthur Marivin, Jorge Barbazán, Fiona Murray, Ulrich Nitsche, Klaus-Peter Janssen, Karl Willert, Ajay Goel, Miguel Abal, Mikel Garcia-Marcos, Pradipta Ghosh

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Abstract

Wnt signaling is essential for tissue homeostasis and its dysregulation causes cancer. Wnt ligands trigger signaling by activating Frizzled receptors (FZDRs), which belong to the G-protein coupled receptor superfamily. However, the mechanisms of G protein activation in Wnt signaling remain controversial. In this study, we demonstrate that FZDRs activate G proteins and trigger non-canonical Wnt signaling via the Dishevelled-binding protein, Daple. Daple contains a Gα-binding and activating (GBA) motif, which activates Gαi proteins and an adjacent domain that directly binds FZDRs, thereby linking Wnt stimulation to G protein activation. This triggers non-canonical Wnt responses, that is, suppresses the β-catenin/TCF/LEF pathway and tumorigenesis, but enhances PI3K-Akt and Rac1 signals and tumor cell invasiveness. In colorectal cancers, Daple is suppressed during adenoma-to-carcinoma transformation and expressed later in metastasized tumor cells. Thus, Daple activates Gαi and enhances non-canonical Wnt signaling by FZDRs, and its dysregulation can impact both tumor initiation and progression to metastasis.

Original language	English
Article number	e07091
Number of pages	40
Journal	eLife
Volume	4
Early online date	30 Jun 2015
DOIs	https://doi.org/10.7554/eLife.07091
Publication status	Published - 30 Jun 2015
Externally published	Yes

Keywords

Frizzled Receptors
Heterotrimeric GTP-Binding Proteins
Humans
Intracellular Signaling Peptides and Proteins
Microfilament Proteins
Wnt Signaling Pathway

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.7554/eLife.07091Licence: CC BY

Daple is a novel non-receptor GEF required for trimeric G protein activation in Wnt signaling
© 2015, Aznar et al This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited
Final published version, 7.36 MBLicence: CC BY

Fiona Murray
Person: Academic

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title = "Daple is a novel non-receptor GEF required for trimeric G protein activation in Wnt signaling",

abstract = "Wnt signaling is essential for tissue homeostasis and its dysregulation causes cancer. Wnt ligands trigger signaling by activating Frizzled receptors (FZDRs), which belong to the G-protein coupled receptor superfamily. However, the mechanisms of G protein activation in Wnt signaling remain controversial. In this study, we demonstrate that FZDRs activate G proteins and trigger non-canonical Wnt signaling via the Dishevelled-binding protein, Daple. Daple contains a Gα-binding and activating (GBA) motif, which activates Gαi proteins and an adjacent domain that directly binds FZDRs, thereby linking Wnt stimulation to G protein activation. This triggers non-canonical Wnt responses, that is, suppresses the β-catenin/TCF/LEF pathway and tumorigenesis, but enhances PI3K-Akt and Rac1 signals and tumor cell invasiveness. In colorectal cancers, Daple is suppressed during adenoma-to-carcinoma transformation and expressed later in metastasized tumor cells. Thus, Daple activates Gαi and enhances non-canonical Wnt signaling by FZDRs, and its dysregulation can impact both tumor initiation and progression to metastasis.",

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AU - Aznar, Nicolas

AU - Midde, Krishna K

AU - Dunkel, Ying

AU - Lopez-Sanchez, Inmaculada

AU - Pavlova, Yelena

AU - Marivin, Arthur

AU - Barbazán, Jorge

AU - Murray, Fiona

AU - Nitsche, Ulrich

AU - Janssen, Klaus-Peter

AU - Willert, Karl

AU - Goel, Ajay

AU - Abal, Miguel

AU - Garcia-Marcos, Mikel

AU - Ghosh, Pradipta

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N2 - Wnt signaling is essential for tissue homeostasis and its dysregulation causes cancer. Wnt ligands trigger signaling by activating Frizzled receptors (FZDRs), which belong to the G-protein coupled receptor superfamily. However, the mechanisms of G protein activation in Wnt signaling remain controversial. In this study, we demonstrate that FZDRs activate G proteins and trigger non-canonical Wnt signaling via the Dishevelled-binding protein, Daple. Daple contains a Gα-binding and activating (GBA) motif, which activates Gαi proteins and an adjacent domain that directly binds FZDRs, thereby linking Wnt stimulation to G protein activation. This triggers non-canonical Wnt responses, that is, suppresses the β-catenin/TCF/LEF pathway and tumorigenesis, but enhances PI3K-Akt and Rac1 signals and tumor cell invasiveness. In colorectal cancers, Daple is suppressed during adenoma-to-carcinoma transformation and expressed later in metastasized tumor cells. Thus, Daple activates Gαi and enhances non-canonical Wnt signaling by FZDRs, and its dysregulation can impact both tumor initiation and progression to metastasis.

AB - Wnt signaling is essential for tissue homeostasis and its dysregulation causes cancer. Wnt ligands trigger signaling by activating Frizzled receptors (FZDRs), which belong to the G-protein coupled receptor superfamily. However, the mechanisms of G protein activation in Wnt signaling remain controversial. In this study, we demonstrate that FZDRs activate G proteins and trigger non-canonical Wnt signaling via the Dishevelled-binding protein, Daple. Daple contains a Gα-binding and activating (GBA) motif, which activates Gαi proteins and an adjacent domain that directly binds FZDRs, thereby linking Wnt stimulation to G protein activation. This triggers non-canonical Wnt responses, that is, suppresses the β-catenin/TCF/LEF pathway and tumorigenesis, but enhances PI3K-Akt and Rac1 signals and tumor cell invasiveness. In colorectal cancers, Daple is suppressed during adenoma-to-carcinoma transformation and expressed later in metastasized tumor cells. Thus, Daple activates Gαi and enhances non-canonical Wnt signaling by FZDRs, and its dysregulation can impact both tumor initiation and progression to metastasis.

KW - Frizzled Receptors

KW - Heterotrimeric GTP-Binding Proteins

KW - Humans

KW - Intracellular Signaling Peptides and Proteins

KW - Microfilament Proteins

KW - Wnt Signaling Pathway

U2 - 10.7554/eLife.07091

DO - 10.7554/eLife.07091

M3 - Article

C2 - 26126266

VL - 4

JO - eLife

JF - eLife

M1 - e07091

ER -

Daple is a novel non-receptor GEF required for trimeric G protein activation in Wnt signaling

Abstract

Keywords

UN SDGs

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Fiona Murray

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