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Paper text:
wnt proteins comprise a large family of secreted glycoproteins that regulate key developmental processes including cell - fate determination , proliferation , motility and the establishment of the primary axis of the body during vertebrate embryogenesis [ 1 - 3 ] .
defects in wnt signaling are also implicated in a host of pathologies including cancer and neural tube defects .
wnt ligands can transform cells , and mutations in components of the wnt signaling pathway , such as -catenin , have causative roles in colon cancers in humans , while mutations in dishevelled ( dsh ) are implicated in neural - fold closure disorders . to date , 18 wnt ligands have been identified in humans .
this large number of ligands is paralleled by an equally impressive number of receptors and co - receptors , which are encoded in the frizzled and low - density - related lipoprotein receptor 5/6 ( lrp5/6 ) gene families , which have ten and two members , respectively , in the human genome . through intensive studies spanning over two decades , a molecular pathway for wnt
signaling has emerged ( figure 1 ) . upon binding of wnt to its receptor , either frizzled or a complex comprising frizzled and lrp5/6 , a signal is transduced to the cytoplasmic phosphoprotein dsh .
there are three dsh proteins in mammals ( dsh-1 , dsh-2 , and dsh-3 ) , and dsh family members in all organisms are comprised of three highly conserved domains : an amino - terminal dix domain ( named for dsh and axin ) , a central pdz domain ( named for postsynaptic density-95 , discs - large and zonula occludens-1 ) , and a carboxy - terminal dep domain ( for dsh , egl-10 and pleckstrin ) . at the level of dsh , the wnt signal branches into three separate pathways , the so - called canonical , non - canonical or planar cell polarity ( pcp ) , and wnt - capathways ( figure 1 ) . in all three pathways dsh
is a key transducer of the wnt signal that operates at the plasma membrane or in the cytoplasm .
but now , a new study   suggests that dsh also functions within the nucleus . to put this study in context
for canonical signaling , which mediates gene induction events ( figure 1a ) , wnt signaling utilizes the dix and pdz domains of dsh to induce the stabilization of cytosolic -catenin ; this allows for cytoplasmic accumulation and subsequent translocation of -catenin into the nucleus .
regulation of -catenin stability is mediated via a complex of proteins including axin , glycogen synthase kinase 3 ( gsk3 ) , gsk3-binding protein ( gbp ) and casein kinase 1 ( ck1 ) . in the absence of wnt stimulation ,
-catenin is targeted for degradation through the proteosomal pathway via the -transducin repeat containing protein ( -trcp ) , but -catenin is stabilized when a wnt signal is received . in the nucleus ,
-catenin forms complexes with members of the lef / tcf family of transcription factors and other factors , and mediates transcription of wnt target genes .
the non - canonical or pcp pathway mediates cell polarity , cell movements during gastrulation , and other processes , by signal transduction through the pdz and dep domains of dsh , leading to a modification of the actin cytoskeleton ( figure 1b ) . at the level of dsh , two independent and parallel pathways
activation of rho requires the formin - homology protein daam1 that binds to the pdz domain of dsh , leads to the activation of the rho - associated kinase rock , and mediates cytoskeletal re - organization .
rac activation is independent of daam1 , requires the dep domain of dsh , and stimulates jun kinase ( jnk ) activity .
other dsh - binding molecules that influence the pcp pathway include strabismus and prickle , but their mechanisms of action remain incompletely understood . the wnt - capathway ( figure 1c )
wnt signaling through frizzled receptors leads to the release of intra - cellular cain a process mediated through heterotrimeric g - proteins and involving numerous other molecules , including phospholipase c ( plc ) , calcium - calmodulin - dependent kinase 2 ( camk2 ) and protein kinase c ( pkc ) .
with such a daunting number of wnt ligands and frizzled receptors , two challenging questions that remain unanswered are whether ( and if so which ) wnt ligands are specific to particular pathways , and how signals are channeled to each pathway .
notably , some wnt ligands are known to activate both canonical and non - canonical pathways such as wnt3a , whereas others such as wnt5a appear to be specific to non - canonical signaling .
equally elusive is the understanding of how the signal is transmitted from the receptor / coreceptor complex to dsh , although two recent studies have revealed a direct interaction between dsh and frizzled .
most importantly , the way in which dsh couples and distributes wnt signaling into the three signaling branches remains at best poorly understood .
dsh occupies a key position at the crossroads of all branches of the wnt signaling cascade .
it has been proposed that both the subcellular localization of dsh and the choice of effector molecules downstream of dsh govern the selectivity of specific pathway activation .
dsh - localization studies in drosophila   and recently caenorhabditis elegans   have shown a correlation between localization of dsh at the membrane and activation of the pcp pathway .
indeed , mutations in the dep domain , which is required for pcp signaling , show impaired membrane localization that is correlated with impaired pcp signaling .
these studies have furthered the hypothesis that the membrane localization of dsh is required for at least one output of wnt signaling .
in unstimulated cells , dsh localizes to punctate vesicular structures in the cytoplasm   by a process that requires the dix domain ; in response to certain wnt ligands , dsh translocates to the plasma membrane or to the perinuclear / nuclear area , and the membrane localization in all cases studied requires the dep domain .
the significance of nuclear / perinuclear localization remained unclear , but it is noteworthy that a number of components of the canonical signaling pathway , such as apc , axin , and gsk3 , appear to traffic between the cytoplasm and the nucleus along with -catenin [ 26 - 28 ] .
this multitude of studies forms the background for the current paper by sokol and colleagues in journal of biology , which identifies two additional domains in dsh that modulate both its subcellular distribution and its ability to activate canonical wnt signaling . the first newly identified domain , located carboxy - terminal to the dep domain , modulates localization of dsh through its action as a nuclear export signal .
dsh protein lacking this domain or harboring a mutation in a critical lysine residue strongly accumulates in the nucleus of both xenopus embryos and cultured mammalian cells .
surprisingly , however , these mutant proteins retain their ability to mediate canonical signaling as effectively as wild - type dsh .
pharmacological agents impeding nuclear export , and cellular fractionation studies , further provide evidence that endogenous dsh enters the nucleus , supporting the view that dsh shuttles between the cytoplasmic and nuclear compartments .
the authors then identified a second domain , located just carboxy - terminal to the pdz domain , that is required for nuclear localization ; the sequence of this domain is atypical for a nuclear localization sequence ( nls ) .
mutation of this second domain abolished nuclear accumulation of dsh in the presence of nuclear export inhibitors and , remarkably , impaired the ability of dsh to induce -catenin stabilization and to transduce the canonical wnt signal .
interestingly , replacement of this atypical nls with the prototypical nls of the t antigen from the simian virus sv40 redirected dsh to the nucleus and largely restored wnt signaling .
the authors further bolster their findings by demonstrating that stimulation of cultured mammalian cells with wnt3a results in the accumulation of a portion of endogenous dsh ( dvl2 in this case ) in / around the nucleus .
so what is the role for dsh in the nucleus and is the wnt field ready to accommodate such a role for dsh ? this new finding   comes as a surprise , because dsh has been studied extensively over the past two decades and its nuclear localization remained unappreciated . to support their conclusions the authors showed that dsh is found in nuclear fractions , but this approach is not fully conclusive for one may argue that dsh exhibits perinuclear localization and co - fractionates with the outer nuclear envelope .
the strongest evidence for a nuclear role for dsh comes from experiments in which nuclear import and export are manipulated , showing that import is critical for function . yet , when the basic conclusion of a nuclear localization and function of dsh is accepted , several questions remain . if dsh function is required in the nucleus for canonical wnt signaling , why is no hyperactivation of the pathway observed by targeting dsh to the nucleus ?
the authors note this point and postulate that a ' steady state ' rather than just localization is required for function .
however , one would at least be compelled to posit that -catenin , which should be stabilized by such dsh - targeted approaches , should increase signaling , and this was not observed . perhaps a more salient question is why many studies have observed dsh translocation to the plasma membrane in response to wnt stimulation or frizzled expression , but have not detected dsh in the nucleus .
it is possible that a small but selective pool of dsh translocates to the nucleus to mediate canonical signaling while most dsh goes to the membrane . yet , if this is the case , is the membrane relocalization of the majority of dsh just a gratuitous cellular behavior without meaning ?
it is possible that nuclear dsh acts in transcriptional regulation independent of -catenin to mediate wnt signaling , as sokol and colleagues have previously suggested for the dsh - binding protein frodo .
perhaps the nuclear localization of dsh will indeed provide clues to elucidate the final frontier of understanding the diverse mechanisms of wnt regulation of gene transcription in the nucleus .
a schematic representation of the wnt signal transduction cascade . ( a ) for the canonical pathway , signaling through the frizzled ( fz ) and lrp5/6 receptor complex induces the stabilization of -catenin via the dix and pdz domains of dishevelled ( dsh ) and a number of factors including axin , glycogen synthase kinase 3 ( gsk3 ) and casein kinase 1 ( ck1 ) .
-catenin translocates into the nucleus where it complexes with members of the lef / tcf family of transcription factors to mediate transcriptional induction of target genes .
( b ) for non - canonical or planar cell polarity ( pcp ) signaling , wnt signaling is transduced through frizzled independent of lpr5/6 . utilizing the pdz and dep domains of dsh , this pathway mediates cytoskeletal changes through activation of the small gtpases rho and rac .
( c ) for the wnt - capathway , wnt signaling via frizzled mediates activation of heterotrimeric g - proteins , which engage dsh , phospholipase c ( plc ; not shown ) , calcium - calmodulin kinase 2 ( camk2 ) and protein kinase c ( pkc ) .
this pathway also uses the pdz and dep domains of dsh to modulate cell adhesion and motility . note that for the pcp and capathways dsh is proposed to function at the membrane , whereas for canonical signaling dsh has been proposed to function in the cytoplasm ; a recent study   implicates nuclear localization of dsh in this pathway
the phosphoprotein dishevelled ( dsh ) is an essential component of wnt signaling pathways and transduces signals into three separate branches , the canonical , non - canonical and ca2 + pathways . 
 how dsh focuses signaling into these branches remains mysterious , but a new study reveals the importance of nuclear localization of dsh for pathway - specific activation .