| Literature References | 1. WODARZ, A. AND NUSSE, R.
Mechanisms of Wnt signal transduction.
ANNU.REV.CELL DEV.BIOL. 14 59-88 (1998).
2. BEJSOVEC, A.
Signal transduction: Wnt signalling shows its versatility.
CURR.BIOL. 9 R684-R687 (1999).
3. DE FERRARI, G.V. AND INESTROSA, N.C.
Wnt signaling function in Alzheimer's disease.
BRAIN RES.BRAIN RES.REV. 33 1-12 (2000).
4. SEMENOV, M.V. AND SNYDER, M.
Human dishevelled genes constitute a DHR-containing multigene family.
GENOMICS 42 302-310 (1997).
5. PEIFER, M. AND POLAKIS, P.
Wnt signalling in oncogenesis and embryogenesis - a look outside the
nucleus.
SCIENCE 287 1606-1609 (2000).
6. MOON, R.T.
An introduction to non-canonical Wnt and Frizzled signaling.
SEMIN.CELL DEV.BIOL. 13 215 (2002).
7. PENTON, A., WODARZ, A. AND NUSSE, R.
A mutational analysis of dishevelled in Drosophila defines novel domains in
the dishevelled protein as well as novel suppressing alleles of axin.
GENETICS 161 747-762 (2002).
8. LEE, J.S., ISHIMOTO, A. AND YANAGAWA, S.
Characterization of mouse dishevelled (Dvl) proteins in Wnt/wingless
signaling pathway.
J.BIOL.CHEM. 274 21464-21470 (1999).
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| Documentation | Wnt proteins constitute a large family of secreted signalling molecules that
are involved in intercellular signalling during development. The name
derives from the first 2 members of the family to be discovered: int-1
(mouse) and wingless (Wg) (Drosophila) [1]. It is now recognised that Wnt
signalling controls many cell fate decisions in a variety of different
organisms, including mammals [2]. Wnt signalling has been implicated in
tumorigenesis, early mesodermal patterning of the embryo, morphogenesis of
the brain and kidneys, regulation of mammary gland proliferation and
Alzheimer's disease [3,4].
Wnt signal transduction proceeds initially via binding to their cell
surface receptors - the so-called frizzled proteins. This activates the
signalling functions of B-catenin and regulates the expression of specific
genes important in development [5]. More recently, however, several non-
canonical Wnt signalling pathways have been elucidated that act
independently of B-catenin [6]. In both cases, the transduction mechanism
requires dishevelled protein (Dsh), a cytoplasmic phosphoprotein that acts
directly downstream of frizzled [7]. In addition to its role in Wnt
signalling, Dsh is also involved in generating planar polarity in Drosophila
and has been implicated in the Notch signal transduction cascade. Three
human and mouse homologues of Dsh have been cloned (DVL-1 to 3); it is
believed that these proteins, like their Drosophila counterpart, are
involved in signal transduction. Human and murine orthologues share more
than 95% sequence identity and are each 40-50% identical to Drosophila Dsh.
Sequence similarity amongst Dsh proteins is concentrated around three
conserved domains: at the N-terminus lies a DIX domain (mutations
mapping to this region reduce or completely disrupt Wg signalling); a PDZ
(or DHR) domain, often found in proteins involved in protein-protein
interactions, lies within the central portion of the protein (point
mutations within this module have been shown to have little effect on
Wg-mediated signal transduction); and a DEP domain is located towards the C-
terminus and is conserved among a set of proteins that regulate various
GTPases (whilst genetic and molecular assays have shown this module to be
dispensible for Wg signalling, it is thought to be important in planar
polarity signalling in flies [7,8]).
DISHEVELLED is a 4-element fingerprint that provides a signature for Dsh
proteins. The fingerprint was derived from an initial alignment of 9
sequences: the motifs were drawn from conserved regions spanning central
and C-terminal portions of the alignment, focusing on those sections that
characterise Dsh proteins but distinguish them from other sequences
that contain the genetically-mobile PDZ domain - motif 1 encodes part of
the C-terminal portion of the PDZ domain; motif 2 lies between the PDZ and
DEP domains; and motifs 3 and 4 reside within the DEP domain. Four
iterations on SPTR40_20f were required to reach convergence, at which point
a true set comprising 17 sequences was identified.
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