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

Research output: Contribution to journalArticle

43 Citations (Scopus)
4 Downloads (Pure)

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 languageEnglish
Article numbere07091
Number of pages40
JournaleLife
Volume4
Early online date30 Jun 2015
DOIs
Publication statusPublished - 30 Jun 2015

Fingerprint

Frizzled Receptors
GTP-Binding Proteins
Chemical activation
Tumors
Neoplasms
Tissue homeostasis
Catenins
Cells
G-Protein-Coupled Receptors
Phosphatidylinositol 3-Kinases
Adenoma
Colorectal Neoplasms
Carrier Proteins
Carcinogenesis
Homeostasis
Neoplasm Metastasis
Ligands
Carcinoma
Proteins

Keywords

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

Cite this

Aznar, N., Midde, K. K., Dunkel, Y., Lopez-Sanchez, I., Pavlova, Y., Marivin, A., ... Ghosh, P. (2015). Daple is a novel non-receptor GEF required for trimeric G protein activation in Wnt signaling. eLife, 4, [e07091]. https://doi.org/10.7554/eLife.07091

Daple is a novel non-receptor GEF required for trimeric G protein activation in Wnt signaling. / Aznar, Nicolas; Midde, Krishna K; Dunkel, Ying; Lopez-Sanchez, Inmaculada; Pavlova, Yelena; Marivin, Arthur; Barbazán, Jorge; Murray, Fiona; Nitsche, Ulrich; Janssen, Klaus-Peter; Willert, Karl; Goel, Ajay; Abal, Miguel; Garcia-Marcos, Mikel; Ghosh, Pradipta.

In: eLife, Vol. 4, e07091, 30.06.2015.

Research output: Contribution to journalArticle

Aznar, N, Midde, KK, Dunkel, Y, Lopez-Sanchez, I, Pavlova, Y, Marivin, A, Barbazán, J, Murray, F, Nitsche, U, Janssen, K-P, Willert, K, Goel, A, Abal, M, Garcia-Marcos, M & Ghosh, P 2015, 'Daple is a novel non-receptor GEF required for trimeric G protein activation in Wnt signaling', eLife, vol. 4, e07091. https://doi.org/10.7554/eLife.07091
Aznar N, Midde KK, Dunkel Y, Lopez-Sanchez I, Pavlova Y, Marivin A et al. Daple is a novel non-receptor GEF required for trimeric G protein activation in Wnt signaling. eLife. 2015 Jun 30;4. e07091. https://doi.org/10.7554/eLife.07091
Aznar, Nicolas ; Midde, Krishna K ; Dunkel, Ying ; Lopez-Sanchez, Inmaculada ; Pavlova, Yelena ; Marivin, Arthur ; Barbazán, Jorge ; Murray, Fiona ; Nitsche, Ulrich ; Janssen, Klaus-Peter ; Willert, Karl ; Goel, Ajay ; Abal, Miguel ; Garcia-Marcos, Mikel ; Ghosh, Pradipta. / Daple is a novel non-receptor GEF required for trimeric G protein activation in Wnt signaling. In: eLife. 2015 ; Vol. 4.
@article{4a7937b33aab4f07b5d6baa6899561de,
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.",
keywords = "Frizzled Receptors, Heterotrimeric GTP-Binding Proteins, Humans, Intracellular Signaling Peptides and Proteins, Microfilament Proteins, Wnt Signaling Pathway",
author = "Nicolas Aznar and Midde, {Krishna K} and Ying Dunkel and Inmaculada Lopez-Sanchez and Yelena Pavlova and Arthur Marivin and Jorge Barbaz{\'a}n and Fiona Murray and Ulrich Nitsche and Klaus-Peter Janssen and Karl Willert and Ajay Goel and Miguel Abal and Mikel Garcia-Marcos and Pradipta Ghosh",
year = "2015",
month = "6",
day = "30",
doi = "10.7554/eLife.07091",
language = "English",
volume = "4",
journal = "eLife",
issn = "2050-084X",
publisher = "eLife Sciences Publications",

}

TY - JOUR

T1 - Daple is a novel non-receptor GEF required for trimeric G protein activation in Wnt signaling

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

PY - 2015/6/30

Y1 - 2015/6/30

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

SN - 2050-084X

M1 - e07091

ER -