描述：
Dickkopf related protein 4 (Dkk-4) is a member of the Dkk protein family that includes
Dkk-1, -2, -3, and -4. All four members are secreted proteins that are synthesized as
precursor proteins with an N-terminal signal peptide and 2 conserved cysteine-rich
domains, which are separated by a linker region. Dkk proteins havepotential furin type
proteolytic cleavage sites, and short forms of Dkk-2 and Dkk-4 containing only the second
cysteine-rich domain can be generated by proteolytic processing. Dkk proteins have distinct
patterns of expression in adult and embryonic tissues, suggesting that they may play diverse
roles in these tissues. The Dkk proteins have distinct effects on Wnt signaling. Dkk-1 and Dkk-4
are Wnt antagonists. Dkk-3 has not been demonstrated to affect Wnt signaling, and Dkk-2
acts as an agonist or antagonist, depending on the cellular context. Wnt signaling regulates
many important developmental processes including neural crest differentiation, brain
development, kidney morphogenesis, and sex determination. In addition, Wnt signaling has
also been implicated in tumor formation. Canonical Wnt signaling via the βcatenin pathway
is transduced by a receptor complex composed of the Frizzled proteins (Fz) and lowdensity
lipoprotein (LDL) receptorrelated proteins (LRP5/6). Unlike many soluble Wnt antagonists that
function by binding extracellular Wnt ligands to prevent interaction of Wnt with the FzLRP5/6
receptor complex, Dkk-1 and Dkk-4 antagonize Wnt/βcatenin signaling by direct highaffinity
binding to the Wnt coreceptor LRP5/6 and inhibiting interaction of LRP5/6 with the Wnt
Frizzled complex. Dkk-1 and Dkk-4 also bind the transmembrane proteins Kremen1 (Krm1)
and Krm2 with highaffinity. Krm2 has been shown to form a ternary complex with Dkk-1 or -4
and LRP5/6 to trigger internalization of the complex and removal of LRP6 from the cell surface.
Thus, Dkk1/4 and Kremens function synergistically to antagonize LRP5/6mediated Wnt activity. Dkk2 also binds to LRP5/6 and the Kremens, but Dkk2 acts as an antagonist of the Wnt
signaling pathway only in the presence of Krm2. Dkk-2 binding to LRP5/6 in the absence of
Krm2 activates rather than inhibits Wnt signalling.
原厂资料：
Dickkopf related protein 4 (Dkk-4) is a member of the Dkk protein family that includes
Dkk-1, -2, -3, and -4. All four members are secreted proteins that are synthesized as
precursor proteins with an N-terminal signal peptide and 2 conserved cysteine-rich
domains, which are separated by a linker region. Dkk proteins havepotential furin type
proteolytic cleavage sites, and short forms of Dkk-2 and Dkk-4 containing only the second
cysteine-rich domain can be generated by proteolytic processing. Dkk proteins have distinct
patterns of expression in adult and embryonic tissues, suggesting that they may play diverse
roles in these tissues. The Dkk proteins have distinct effects on Wnt signaling. Dkk-1 and Dkk-4
are Wnt antagonists. Dkk-3 has not been demonstrated to affect Wnt signaling, and Dkk-2
acts as an agonist or antagonist, depending on the cellular context. Wnt signaling regulates
many important developmental processes including neural crest differentiation, brain
development, kidney morphogenesis, and sex determination. In addition, Wnt signaling has
also been implicated in tumor formation. Canonical Wnt signaling via the βcatenin pathway
is transduced by a receptor complex composed of the Frizzled proteins (Fz) and lowdensity
lipoprotein (LDL) receptorrelated proteins (LRP5/6). Unlike many soluble Wnt antagonists that
function by binding extracellular Wnt ligands to prevent interaction of Wnt with the FzLRP5/6
receptor complex, Dkk-1 and Dkk-4 antagonize Wnt/βcatenin signaling by direct highaffinity
binding to the Wnt coreceptor LRP5/6 and inhibiting interaction of LRP5/6 with the Wnt
Frizzled complex. Dkk-1 and Dkk-4 also bind the transmembrane proteins Kremen1 (Krm1)
and Krm2 with highaffinity. Krm2 has been shown to form a ternary complex with Dkk-1 or -4
and LRP5/6 to trigger internalization of the complex and removal of LRP6 from the cell surface.
Thus, Dkk1/4 and Kremens function synergistically to antagonize LRP5/6mediated Wnt activity. Dkk2 also binds to LRP5/6 and the Kremens, but Dkk2 acts as an antagonist of the Wnt
signaling pathway only in the presence of Krm2. Dkk-2 binding to LRP5/6 in the absence of
Krm2 activates rather than inhibits Wnt signalling.
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