Cdo Functions at Multiple Points in the Sonic Hedgehog Pathway, and Cdo-Deficient Mice Accurately Model Human Holoprosencephaly

Zhang, Wei; Kang, Jong Sun; Cole, Francesca; Yi, Min Jeong; Krauss, Robert M.

doi:10.1016/j.devcel.2006.04.005

Cited by 234 publications

(281 citation statements)

References 37 publications

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“…NIH 3T3 cells express low levels of Cdo (35), and clustering of JLP-GFP, Bnip-2-GFP, and wGBD-GFP at Ncad beads was largely dependent on coexpression of nonfluorescent Cdo [ Fig. 4 D and E; note that the exogenous expression levels of Cdo-GFP and nonfluorescent Cdo were similar (Fig.…”

Section: Resultsmentioning

confidence: 99%

N-cadherin ligation, but not Sonic hedgehog binding, initiates Cdo-dependent p38α/β MAPK signaling in skeletal myoblasts

Lü

Krauss

2010

Proc. Natl. Acad. Sci. U.S.A.

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The p38α/β mitogen-activated protein kinase (MAPK) pathway promotes muscle-specific gene expression and myoblast differentiation but how pathway activity is initiated during these processes is poorly understood. During myoblast differentiation, the intracellular region of the promyogenic cell surface protein Cdo (also known as Cdon) binds to Bnip-2 and JLP, scaffold proteins for Cdc42 and p38α/β MAPK, respectively. The Bnip-2/Cdc42 and JLP/p38α/β complexes associate in a Cdo-dependent manner, resulting in Bnip-2/Cdc42-dependent p38α/β activation and stimulation of cell differentiation. Although the Cdo ectodomain binds to several different proteins, it is unclear how Cdo-dependent p38α/β activation is initiated. In myoblasts, Cdo interacts with the cell–cell adhesion molecule N-cadherin. Cdo also binds directly to the secreted morphogen Sonic hedgehog (Shh) to promote Shh pathway signaling. We report here that N-cadherin ligation activates p38α/β in myoblasts in a Cdo-, Bnip-2-, and JLP-dependent manner. Furthermore, these proteins and activated Cdc42 cluster at sites of N-cadherin ligation. In contrast, neither JLP nor Bnip-2 is associated with Cdo bound to Shh, and Shh does not activate p38α/β in myoblasts. Taken together, these results link cadherin-based cell–cell adhesion to a defined signaling pathway (Cdo → p38α/β) that directly regulates a cell-type-specific differentiation program. Furthermore, they are consistent with a model whereby Cdo serves as a multifunctional coreceptor with mechanistically distinct roles in multiple signaling pathways.

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Section: Resultsmentioning

confidence: 99%

N-cadherin ligation, but not Sonic hedgehog binding, initiates Cdo-dependent p38α/β MAPK signaling in skeletal myoblasts

Lü

Krauss

2010

Proc. Natl. Acad. Sci. U.S.A.

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“…Hhinteracting protein (HIP) can compete with PTC in Hh binding to inhibit Hh signaling (Chuang and McMahon, 1999). Additional molecules, Ihog (or its vertebrate homologs CDO and BOC), GAS1 and Glypican-3, are also able to bind Hh (Okada et al, 2006;Tenzen et al, 2006;Yao et al, 2006;Zhang et al, 2006;Allen et al, 2007;Martinelli and Fan, 2007;Seppala et al, 2007;Capurro et al, 2008) although the Hh-Ihog binding mode is very different from Shh-CDO interaction (McLellan et al, 2008). It is still not entirely clear how binding of Hh proteins results in the pathway activation.…”

Section: Signal Transduction Of the Hedgehog Pathwaymentioning

confidence: 99%

Activation of the hedgehog-signaling pathway in human cancer and the clinical implications

et al. 2009

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“…Recently, Ihog (interference Hh) and Boi, which de-repress SMO through interaction with Hh ligands, have been identified in Drosophila (Yao et al, 2006). Their mouse/ human homologues Boc/BOC and Cdo/CDO have the same functions (Tenzen et al, 2006;Yao et al, 2006;Zhang et al, 2006).…”

mentioning

confidence: 99%

Cross talk between hedgehog and epithelial–mesenchymal transition pathways in gastric pit cells and in diffuse-type gastric cancers

Ohta

Aoyagi²,

Fukaya³

et al. 2008

Br J Cancer

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We previously reported hedgehog (Hh) signal activation in the mucus-secreting pit cell of the stomach and in diffuse-type gastric cancer (GC). Epithelial -mesenchymal transition (EMT) is known to be involved in tumour malignancy. However, little is known about whether and how both signallings cooperatively act in diffuse-type GC. By microarray and reverse transcription -PCR, we investigated the expression of those Hh and EMT signalling molecules in pit cells and in diffuse-type GCs. How both signallings act cooperatively in those cells was also investigated by the treatment of an Hh-signal inhibitor and siRNAs of Hh and EMT transcriptional key regulator genes on a mouse primary culture and on human GC cell lines. Pit cells and diffuse-type GCs co-expressed many Hh and EMT signalling genes. Mesenchymal-related genes (WNT5A, CDH2, PDGFRB, EDNRA, ROBO1, ROR2, and MEF2C) were found to be activated by an EMT regulator, SIP1/ZFHX1B/ZEB2, which was a target of a primary transcriptional regulator GLI1 in Hh signal. Furthermore, we identified two cancer-specific Hh targets, ELK1 and MSX2, which have an essential role in GC cell growth. These findings suggest that the gastric pit cell exhibits mesenchymal-like gene expression, and that diffuse-type GC maintains expression through the Hh -EMT pathway. Our proposed extensive Hh -EMT signal pathway has the potential to an understanding of diffusetype GC and to the development of new drugs.

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Cdo Functions at Multiple Points in the Sonic Hedgehog Pathway, and Cdo-Deficient Mice Accurately Model Human Holoprosencephaly

Cited by 234 publications

References 37 publications

N-cadherin ligation, but not Sonic hedgehog binding, initiates Cdo-dependent p38α/β MAPK signaling in skeletal myoblasts

N-cadherin ligation, but not Sonic hedgehog binding, initiates Cdo-dependent p38α/β MAPK signaling in skeletal myoblasts

Activation of the hedgehog-signaling pathway in human cancer and the clinical implications

Cross talk between hedgehog and epithelial–mesenchymal transition pathways in gastric pit cells and in diffuse-type gastric cancers

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