scholarly journals Signal transduction by the Wnt family of ligands

1998 ◽  
Vol 329 (2) ◽  
pp. 209-223 ◽  
Author(s):  
C. Trevor DALE
Keyword(s):  
Signal Transduction ◽  
Cell Fate ◽  
Recent Progress ◽  
Cell Communication ◽  
Signal Transduction Pathway ◽  
Interdisciplinary Approach ◽  
Large Family ◽  
Wnt Signalling ◽  
Intracellular Signalling Pathway ◽  
Mediate Cell

The Wnt genes encode a large family of secreted polypeptides that mediate cell-cell communication in diverse developmental processes. The loss or inappropriate activation of Wnt expression has been shown to alter cell fate, morphogenesis and mitogenesis. Recent progress has identified Wnt receptors and components of an intracellular signalling pathway that mediate Wnt-dependent transcription. This review will highlight this ‘core’ Wnt signal-transduction pathway, but also aims to reveal the potential diversity of Wnt signalling targets. Particular attention will be paid to the overlap between developmental biology and oncogenesis, since recent progress shows Wnt signalling forms a paradigm for an interdisciplinary approach.

Novel pathway for thyroid hormone receptor action through interaction with jun and fos oncogene activities

1991 ◽  
Vol 11 (12) ◽  
pp. 6016-6025
Author(s):  
X K Zhang ◽  
K N Wills ◽  
M Husmann ◽  
T Hermann ◽  
M Pfahl
Keyword(s):  
Signal Transduction ◽  
Dna Binding ◽  
Thyroid Hormone Receptor ◽  
Gene Activation ◽  
Signal Transduction Pathway ◽  
Large Family ◽  
Transduction Pathway ◽  
Regulatory Pathway

Many essential biological pathways, including cell growth, development, and metabolism, are regulated by thyroid hormones (THs). TH action is mediated by intracellular receptors that belong to a large family of ligand-dependent transcription factors, including the steroid hormone and retinoic acid receptors. So far it has been assumed that TH receptors (TRs) regulate gene transcription only through the classical protein-DNA interaction mechanism. Here we provide evidence for a regulatory pathway that allows cross-talk between TRs and the signal transduction pathway used by many growth factors, oncogenes, and tumor promoters. In transient transfection studies, we observed that the oncogenes c-jun and c-fos inhibit TR activities, while TRs inhibit induction of the c-fos promoter and repress AP-1 site-dependent gene activation. A truncated TR that lacks only 17 amino acids from the carboxy terminus can no longer antagonize AP-1 activity. The cross-regulation between TRs and the signal transduction pathway appears to be based on the ability of TRs to inhibit DNA binding of the transcription factor AP-1 in the presence of THs. The constituents of AP-1, c-Jun, and c-Fos, vice versa, can inhibit TR-induced gene activation in vivo, and c-Jun inhibits TR DNA binding in vitro. This novel regulatory pathway is likely to play a major role in growth control and differentiation by THs.

TCF: Lady Justice Casting the Final Verdict on the Outcome of Wnt Signalling

2002 ◽  
Vol 383 (2) ◽  
pp. 255-261 ◽  
Author(s):  
H. Brantjes ◽  
N. Barker ◽  
J. van Es ◽  
H. Clevers
Keyword(s):  
Cell Fate ◽  
Target Genes ◽  
Signal Transduction Pathway ◽  
Wnt Signalling ◽  
Early Event ◽  
Embryonic Patterning ◽  
Repressor Proteins ◽  
Downstream Effectors ◽  
Signalling Cascade

Abstract The Wnt signalling cascade plays an important role during embryonic patterning and cell fate determination and is highly conserved throughout evolution. Factors of the TCF/LEF HMG domain family (Tcfs) are the downstream effectors of this signal transduction pathway. Upon Wnt signalling, a cascade is initiated that results in the translocation of βcatenin to the nucleus, where it interacts with Tcf to generate a transcriptionally active complex. This bipartite transcription factor is targeted to the upstream regulatory regions of Tcf target genes. In the absence of Wnt signals, βcatenin is degraded in the cytoplasm via the ubiquitinproteasome pathway. Several proteins are instrumental in achieving this tight regulation of βcatenin levels in the cell, including adenomatous polyposis coli (APC), GSK3 β, and Axin/Conductin. Deregulation of the Wnt signalling pathway is implicated in several forms of cancer, such as colon carcinoma and melanoma. This deregulation is achieved via mutation of APC, βcatenin or Axin, resulting in elevated βcatenin levels and the presence of constitutively active Tcfβcatenin complexes in the nucleus. The accompanying inappropriate activation of target genes is considered to be a critical, early event in this carcinogenesis. In addition to regulating βcatenin levels, normal healthy cells have evolved a second level of regulation, by manipulating the activity of the Tcf proteins themselves. In the absence of Wnt signalling, Tcf complexes with several transcriptional repressor proteins ensuring active repression of Tcf target genes. In this review the dual role of Tcf proteins in the Wnt signalling cascade will be discussed.

scholarly journals Gain-of-Function Mutations in the Caenorhabditis elegans lin-1 ETS Gene Identify a C-Terminal Regulatory Domain Phosphorylated by ERK MAP Kinase

Genetics ◽  
1998 ◽  
Vol 149 (4) ◽  
pp. 1809-1822 ◽  
Author(s):  
Dave Jacobs ◽  
Greg J Beitel ◽  
Scott G Clark ◽  
H Robert Horvitz ◽  
Kerry Kornfeld
Keyword(s):  
Signal Transduction ◽  
Caenorhabditis Elegans ◽  
Tyrosine Kinase ◽  
Map Kinase ◽  
Cell Fate ◽  
Receptor Tyrosine Kinase ◽  
Signal Transduction Pathway ◽  
Negative Regulation ◽  
Transduction Pathway ◽  
C Terminus

Abstract Genetic analysis of lin-1 loss-of-function mutations suggests that lin-1 controls multiple cell-fate decisions during Caenorhabditis elegans development and is negatively regulated by a conserved receptor tyrosine kinase-Ras-ERK mitogen-activated protein (MAP) kinase signal transduction pathway. LIN-1 protein contains an ETS domain and presumably regulates transcription. We identified and characterized six gain-of-function mutations that define a new class of lin-1 allele. These lin-1 alleles appeared to be constitutively active and unresponsive to negative regulation. Each allele has a single-base change that affects the predicted C terminus of LIN-1, suggesting this region is required for negative regulation. The C terminus of LIN-1 was a high-affinity substrate for Erk2 in vitro, suggesting that LIN-1 is directly regulated by ERK MAP kinase. Because mpk-1 ERK MAP kinase controls at least one cell-fate decision that does not require lin-1, our results suggest that MPK-1 contributes to the specificity of this receptor tyrosine kinase-Ras-MAP kinase signal transduction pathway by phosphorylating different proteins in different developmental contexts. These lin-1 mutations all affect a four-amino-acid motif, FQFP, that is conserved in vertebrate and Drosophila ETS proteins that are also phosphorylated by ERK MAP kinase. This sequence may be a substrate recognition motif for the ERK subfamily of MAP kinases.

scholarly journals Novel pathway for thyroid hormone receptor action through interaction with jun and fos oncogene activities.

1991 ◽  
Vol 11 (12) ◽  
pp. 6016-6025 ◽  
Author(s):  
X K Zhang ◽  
K N Wills ◽  
M Husmann ◽  
T Hermann ◽  
M Pfahl
Keyword(s):  
Signal Transduction ◽  
Dna Binding ◽  
Thyroid Hormone Receptor ◽  
Gene Activation ◽  
Signal Transduction Pathway ◽  
Large Family ◽  
Transduction Pathway ◽  
Regulatory Pathway

Many essential biological pathways, including cell growth, development, and metabolism, are regulated by thyroid hormones (THs). TH action is mediated by intracellular receptors that belong to a large family of ligand-dependent transcription factors, including the steroid hormone and retinoic acid receptors. So far it has been assumed that TH receptors (TRs) regulate gene transcription only through the classical protein-DNA interaction mechanism. Here we provide evidence for a regulatory pathway that allows cross-talk between TRs and the signal transduction pathway used by many growth factors, oncogenes, and tumor promoters. In transient transfection studies, we observed that the oncogenes c-jun and c-fos inhibit TR activities, while TRs inhibit induction of the c-fos promoter and repress AP-1 site-dependent gene activation. A truncated TR that lacks only 17 amino acids from the carboxy terminus can no longer antagonize AP-1 activity. The cross-regulation between TRs and the signal transduction pathway appears to be based on the ability of TRs to inhibit DNA binding of the transcription factor AP-1 in the presence of THs. The constituents of AP-1, c-Jun, and c-Fos, vice versa, can inhibit TR-induced gene activation in vivo, and c-Jun inhibits TR DNA binding in vitro. This novel regulatory pathway is likely to play a major role in growth control and differentiation by THs.

scholarly journals Difference in XTcf-3 dependency accounts for change in response to β-catenin-mediated Wnt signalling in Xenopus blastula

Development ◽  
2001 ◽  
Vol 128 (11) ◽  
pp. 2063-2073 ◽  
Author(s):  
Fiona S. Hamilton ◽  
Grant N. Wheeler ◽  
Stefan Hoppler
Keyword(s):  
Signal Transduction ◽  
Signal Transduction Pathway ◽  
Wnt Signalling ◽  
Signal Transduction Pathways ◽  
Tissue Specific ◽  
Animal Development ◽  
Specific Effects ◽  
Early Embryos ◽  
Dramatic Shift ◽  
Canonical Wnt

Wnt signalling functions in many tissues and during different stages of animal development to produce very specific responses. In early Xenopus embryos there is a dramatic change in response to Wnt signalling within only a few hours of development. Wnt signalling in very early embryos leads to a dorsalising response, which establishes the endogenous dorsal axis. Only a few hours later in development, almost the opposite happens: Xwnt-8 functions to pattern the embryonic mesoderm by promoting ventral and lateral mesoderm. The specificity of the response could conceivably be carried out by differential use of different signal transduction pathways, many of which have recently been described. We have found, however, that this dramatic shift in response to Wnt signalling in early Xenopus is not brought about by differential use of distinct signal transduction pathways. In fact β-catenin, a downstream component of the canonical Wnt signal transduction pathway, functions not only in the early dorsalising response but also in the later ventrolateral-promoting response. Interaction of β-catenin with the XTcf-3 transcription factor is required for the early dorsalising activity. In contrast, our experiments suggest that late Wnt signalling in the ventrolateral mesoderm does not require a similar dependency of β-catenin function on XTcf-3. Our results highlight the potential versatility of the canonical Wnt pathway to interact with tissue-specific factors downstream of β-catenin, in order to achieve tissue-specific effects.

Cross-regulation of the Wnt signalling pathway: a role of MAP kinases

2000 ◽  
Vol 113 (6) ◽  
pp. 911-919 ◽  
Author(s):  
J. Behrens
Keyword(s):  
Map Kinase ◽  
Cell Fate ◽  
Map Kinases ◽  
Target Genes ◽  
Signal Transduction Pathway ◽  
Wnt Signalling ◽  
Beta Catenin ◽  
Fate Decision ◽  
Wnt Signal

The Wnt signal transduction pathway regulates various aspects of embryonal development and is involved in cancer formation. Wnts induce the stabilisation of cytosolic (beta)-catenin, which then associates with TCF transcription factors to regulate expression of Wnt-target genes. At various levels the Wnt pathway is subject to cross-regulation by other components. Recent evidence suggests that a specific MAP kinase pathway involving the MAP kinase kinase kinase TAK1 and the MAP kinase NLK counteract Wnt signalling. In particular, homologues of TAK1 and NLK, MOM-4 and LIT-1, negatively regulate Wnt-controlled cell fate decision in the early Caenorhabditis elegans embryo. Moreover, TAK1 activates NLK, which phosphorylates TCFs bound to (beta)-catenin. This blocks nuclear localization and DNA binding of TCFs. Since TAK1 is activated by TGF-(beta) and various cytokines, it might provide an entry point for regulation of the Wnt system by other pathways. In addition, alterations in TAK1-NLK might play a role in cancer.

Genetic analysis of the sevenless signal transduction pathway of Drosophila

Development ◽  
1993 ◽  
Vol 119 (Supplement) ◽  
pp. 41-46 ◽  
Author(s):  
E. Hafen ◽  
B. Dickson ◽  
T. Raabe ◽  
D. Brunner ◽  
N. Oellers ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Cell Fate ◽  
Receptor Tyrosine Kinase ◽  
Photoreceptor Cell ◽  
Signal Transduction Pathway ◽  
Signal Transduction Pathways ◽  
Transduction Pathway ◽  
Genetic Screens ◽  
Constitutive Activation

The specification of the R7 photoreceptor cell fate in the developing eye of Drosophila depends on the local activation of the sevenless (sev) receptor tyrosine kinase (RTK) by boss, a protein expressed on the membrane of the neighboring R8 cell. Constitutive activation of the scv receptor results in a dosage dependent increase in the number of R7 cells per ommatidium. Genetic screens have been used to identify mutations that alter the efficiency of signal transduction. Subsequent molecular characterization of the corresponding genes has led to the identification of a number of proteins involved in transducing the signal from the receptor to the nucleus. In contrast to the receptor and its ligand, these components are shared between different signal transduction pathways not only in Drosophila but homologous components are also involved in signal transduction in other organisms.

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