2
R. Nusse et al.
examples of genes found to control normal growth but to cause cancerous growth when misregulated. One of the best examples is the Wnt
gene family. We will summarize our current view of how Wnt proteins
signal, and the evidence that proteins of the Frizzled (Fz) family mediate
Wnt signaling by acting as specific cell surface receptors.
1.2 Wingless in Drosophila and Other Wnt Genes
Wnt genes are implicated in numerous developmental processes, as well
as in cancer. The Drosophila Wnt gene wingless (wg) controls many
developmental steps and is important for the growth and patterning of
tissues, for example the imaginal discs. The Drosophila genome contains three other Wnts, as far as is known. All members of the Wnt
family encode secreted signaling proteins with one or several N-linked
glycosylation sites and many cysteine residues (reviewed in Cadigan
and Nusse 1997).
A key step in Wg signaling is mediated by the Armadillo (Arm)
protein. Arm is a homolog of the cell junction protein ~-catenin but it
can also form a complex with a TCF protein. This complex is thought to
activate transcription of downstream genes. (Behrens et al. 1996; Miller
and Moon 1996; Molenaar et al. 1996). Mutant forms of Arm, as found
in several human tumors, can act as constitutively active transcriptional
activators (reviewed in Nusse 1997; Peifer 1997).
1.3 In Vitro Assays for W g Protein
and Receptor Identification
The genetic screens in Drosophila did not yield a candidate gene for a
specific cell surface receptor for W g; a void now explained by genetic
redundancy (see below). Suitable cell culture assays for signaling by W g
and other Wnt proteins have been notoriously difficult, because of
problems in handling Wnt proteins in vitro, complicating receptor identification by biochemical tools. It was therefore important that we found
that W g protein is present in soluble form in the medium of transfected
Drosophila S2 cells and elevates the concentration of the Arm protein in
R. Nusse et al.
examples of genes found to control normal growth but to cause cancerous growth when misregulated. One of the best examples is the Wnt
gene family. We will summarize our current view of how Wnt proteins
signal, and the evidence that proteins of the Frizzled (Fz) family mediate
Wnt signaling by acting as specific cell surface receptors.
1.2 Wingless in Drosophila and Other Wnt Genes
Wnt genes are implicated in numerous developmental processes, as well
as in cancer. The Drosophila Wnt gene wingless (wg) controls many
developmental steps and is important for the growth and patterning of
tissues, for example the imaginal discs. The Drosophila genome contains three other Wnts, as far as is known. All members of the Wnt
family encode secreted signaling proteins with one or several N-linked
glycosylation sites and many cysteine residues (reviewed in Cadigan
and Nusse 1997).
A key step in Wg signaling is mediated by the Armadillo (Arm)
protein. Arm is a homolog of the cell junction protein ~-catenin but it
can also form a complex with a TCF protein. This complex is thought to
activate transcription of downstream genes. (Behrens et al. 1996; Miller
and Moon 1996; Molenaar et al. 1996). Mutant forms of Arm, as found
in several human tumors, can act as constitutively active transcriptional
activators (reviewed in Nusse 1997; Peifer 1997).
1.3 In Vitro Assays for W g Protein
and Receptor Identification
The genetic screens in Drosophila did not yield a candidate gene for a
specific cell surface receptor for W g; a void now explained by genetic
redundancy (see below). Suitable cell culture assays for signaling by W g
and other Wnt proteins have been notoriously difficult, because of
problems in handling Wnt proteins in vitro, complicating receptor identification by biochemical tools. It was therefore important that we found
that W g protein is present in soluble form in the medium of transfected
Drosophila S2 cells and elevates the concentration of the Arm protein in