J Cell Mol Med
April 1, 2008;
The functions and possible significance of Kremen as the gatekeeper of Wnt signalling in development and pathology.
(Krm) was originally discovered as a novel transmembrane protein containing the kringle domain. Both Krm1
(the first identified Krm) and its relative Krm2
were later identified to be the high-affinity receptors for Dickkopf (Dkk
), the inhibitor of Wnt/beta-catenin signalling. The formation of a ternary complex composed of Krm, Dkk
, and Lrp5
/6 (the coreceptor of Wnt) inhibits Wnt/beta-catenin signalling. In Xenopus gastrula
embryos, Wnt/beta-catenin signalling regulates anterior
patterning, with low-signalling in anterior
regions. Inhibition of Krm1
/2 induces embryonic head
defects. Together with anterior
localization of Krms and Dkks, the inhibition of Wnt signalling by Dkk
-Krm action seems to allow anterior
embryonic development. During mammalian development, krm1
mRNA expression is low in the early stages, but gradually and continuously increases with developmental progression and differentiation. In contrast with the wide, strong expression of krm1
mRNA in mature tissues, expression of krm1
is diminished in a variety of human tumor cells. Since stem cells and undifferentiated cells rely on Wnt/beta-catenin signalling for maintenance in a low differentiation state, the physiological shutdown of Wnt/beta-catenin signalling by Dkk
-Krm is likely to set cells on a divergent path toward differentiation. In tumour cells, a deficit of Krm may increase the susceptibility to tumourigenic transformation. Both positive and negative regulation of Wnt/beta-catenin signalling definitively contributes to diverse developmental and physiological processes, including cell-fate determination, tissue
patterning and stem cell
regulation. Krm is quite significant in these processes as the gatekeeper of the Wnt/beta-catenin signalling pathway.
J Cell Mol Med
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References [+] :
1. Schematic structures of kringle domain and Krm.(A) The kringle domain and localization of a variable/unique stretch of 5 or 6 amino acids (blue circles) surrounded by two highly conserved sequences (yellow circles).(B) Multiple alignments of amino acid sequences of two highly conserved sequences that surround a variable region of the kringle domain. Two highly conserved sequences are boxed with yellow. (C) Outline for comprehensive analysis of partial cDNA fragments for kringle-containing proteins. PCR-amplified kringle tags are concatenated and ligated into the cloning plasmid. For details, see Nakamura et al..(D) Schematic representation of the two transmembrane proteins containing kringle domain, Krm and Ror.
2. Regulation of Wnt/-catenin signalling pathway.(A) Wnt forms a ternary complex with Fz and Lrp5/6, which promotes stabilization of β-catenin, thereby activating the pathway. (B) Dkk1 forms a ternary complex with Lrp5/6 and Krm, which blocks Wnt signal transduction by causing endocytosis of Lrp5/6. (C) Ror is the receptor for Wnt5a and blocks Wnt/-catenin signalling by inhibiting β-catenin-dependent gene transcription. (D) WIF and sFRP antagonize the binding of Wnt to Fz.
3. Spatial expression patterns of krm1 mRNA in mouse embryo. (A–C) In situ hybridization of E10.5 mouse whole embryo. Lateral (A), dorsal (B) and ventral (C) view of embryo.(D) Schematic representation of E12.5 and E13.5 mouse embryos. Lines indicate the level of the sections shown in E–H, respectively. (E–H) In situ hybridization of E12.5 and E13.5 mouse transverse sections. E–H show the rostral and the lumbar level sections of E12.5 mouse embryo and the rostral and the lumbar level sections of E13.5 mouse embryo, respectively. AER, apical ectodermal ridge;fl, forelimb bud; h, heart; hl, hindlimb bud; l, lung;np, nasal pit;op, optic vesicle; ot, otic vesicle;fp, floor plate.
4. (A) Expressions of krm1 mRNA in whole mouse embryos at serial developmental stages.(B) Tissue distribution of krm1 mRNA in adult mouse.(C) Change in the expression of krm1 mRNA during myogenic differentiation in C2C12 cells. Expression of krm1 mRNA in C2C12 cells cultured for various periods under conditions permissive for differentiation was analysed.(D) Expressions of krm1 mRNA in human cancer cell lines.
5. Putative model involved in constitutively active Wnt/β-catenin signalling in cancer cells, from the aspect of decreased or diminished Krm expression. In normal cells, cytoplasmic β-catenin level is bi-directionally regulated by the complex formations between Lrp5/6-Wnt-Fz and Lrp5/6-Dkk-Krm. In contrast, in cancer cells, the decreased or diminished expression of Krm allows constitutive accumulation of β-catenin, leading to abnormal Wnt/β-catenin signalling.
Afzal, Recessive Robinow syndrome, allelic to dominant brachydactyly type B, is caused by mutation of ROR2. 2000, Pubmed