Nakamura T , Nakamura T , Matsumoto K .

	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.[3].(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

Afzal, Recessive Robinow syndrome, allelic to dominant brachydactyly type B, is caused by mutation of ROR2. 2000, Pubmed
Aguilera, Epigenetic inactivation of the Wnt antagonist DICKKOPF-1 (DKK-1) gene in human colorectal cancer. 2006, Pubmed
Barandon, Reduction of infarct size and prevention of cardiac rupture in transgenic mice overexpressing FrzA. 2003, Pubmed
Barrow, Ectodermal Wnt3/beta-catenin signaling is required for the establishment and maintenance of the apical ectodermal ridge. 2003, Pubmed
Bienz, Linking colorectal cancer to Wnt signaling. 2000, Pubmed
Binnerts, R-Spondin1 regulates Wnt signaling by inhibiting internalization of LRP6. 2007, Pubmed
Bodine, The Wnt antagonist secreted frizzled-related protein-1 is a negative regulator of trabecular bone formation in adult mice. 2004, Pubmed
Bork, The CUB domain. A widespread module in developmentally regulated proteins. 1993, Pubmed
Boyden, High bone density due to a mutation in LDL-receptor-related protein 5. 2002, Pubmed
Cadigan, Wnt signaling: complexity at the surface. 2006, Pubmed
Caneparo, Dickkopf-1 regulates gastrulation movements by coordinated modulation of Wnt/beta catenin and Wnt/PCP activities, through interaction with the Dally-like homolog Knypek. 2007, Pubmed , Xenbase
Clevers, Wnt/beta-catenin signaling in development and disease. 2006, Pubmed
Davidson, Kremen proteins interact with Dickkopf1 to regulate anteroposterior CNS patterning. 2002, Pubmed , Xenbase
Dean, Canonical Wnt signaling negatively regulates branching morphogenesis of the lung and lacrimal gland. 2005, Pubmed
DeChiara, Ror2, encoding a receptor-like tyrosine kinase, is required for cartilage and growth plate development. 2000, Pubmed
De Langhe, Dickkopf-1 (DKK1) reveals that fibronectin is a major target of Wnt signaling in branching morphogenesis of the mouse embryonic lung. 2005, Pubmed
Foley, Heart induction by Wnt antagonists depends on the homeodomain transcription factor Hex. 2005, Pubmed , Xenbase
Forrester, A C. elegans Ror receptor tyrosine kinase regulates cell motility and asymmetric cell division. 1999, Pubmed
Galli, Porcupine-mediated lipid-modification regulates the activity and distribution of Wnt proteins in the chick neural tube. 2007, Pubmed
Glinka, Dickkopf-1 is a member of a new family of secreted proteins and functions in head induction. 1998, Pubmed , Xenbase
Gong, LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. 2001, Pubmed
Greco, Analysis of the vestigial tail mutation demonstrates that Wnt-3a gene dosage regulates mouse axial development. 1996, Pubmed
Hardt, Glycogen synthase kinase-3beta: a novel regulator of cardiac hypertrophy and development. 2002, Pubmed
He, LDL receptor-related proteins 5 and 6 in Wnt/beta-catenin signaling: arrows point the way. 2004, Pubmed
He, Neuropilin is a receptor for the axonal chemorepellent Semaphorin III. 1997, Pubmed
He, A monoclonal antibody against Wnt-1 induces apoptosis in human cancer cells. 2004, Pubmed
Huelsken, beta-Catenin controls hair follicle morphogenesis and stem cell differentiation in the skin. 2001, Pubmed
Ikeya, Wnt signalling required for expansion of neural crest and CNS progenitors. 1997, Pubmed
Ishikawa, Mouse Wnt receptor gene Fzd5 is essential for yolk sac and placental angiogenesis. 2001, Pubmed , Xenbase
Ito, Wnt-dependent de novo hair follicle regeneration in adult mouse skin after wounding. 2007, Pubmed
Jordan, Wnt4 overexpression disrupts normal testicular vasculature and inhibits testosterone synthesis by repressing steroidogenic factor 1/beta-catenin synergy. 2003, Pubmed
Kahler, Lymphoid enhancer factor-1 and beta-catenin inhibit Runx2-dependent transcriptional activation of the osteocalcin promoter. 2003, Pubmed
Kato, Cbfa1-independent decrease in osteoblast proliferation, osteopenia, and persistent embryonic eye vascularization in mice deficient in Lrp5, a Wnt coreceptor. 2002, Pubmed
Kawano, Secreted antagonists of the Wnt signalling pathway. 2003, Pubmed , Xenbase
Kazanskaya, The role of Xenopus dickkopf1 in prechordal plate specification and neural patterning. 2000, Pubmed , Xenbase
Kikuchi, Multiplicity of the interactions of Wnt proteins and their receptors. 2007, Pubmed
Kim, Wnt inhibitory factor inhibits lung cancer cell growth. 2007, Pubmed
Kinzler, Lessons from hereditary colorectal cancer. 1996, Pubmed
Kinzler, Identification of FAP locus genes from chromosome 5q21. 1991, Pubmed
Kohn, Wnt and calcium signaling: beta-catenin-independent pathways. 2005, Pubmed
Kolodkin, Neuropilin is a semaphorin III receptor. 1997, Pubmed
Korinek, Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4. 1998, Pubmed
Koyanagi, Non-canonical Wnt signaling enhances differentiation of human circulating progenitor cells to cardiomyogenic cells. 2005, Pubmed
Krishnan, Regulation of bone mass by Wnt signaling. 2006, Pubmed
Lee, A local Wnt-3a signal is required for development of the mammalian hippocampus. 2000, Pubmed
Li, Dkk2 has a role in terminal osteoblast differentiation and mineralized matrix formation. 2005, Pubmed
Li, Wnt5a participates in distal lung morphogenesis. 2002, Pubmed
Liang, Wnt5a inhibits B cell proliferation and functions as a tumor suppressor in hematopoietic tissue. 2003, Pubmed
Little, A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait. 2002, Pubmed
Liu, Mutations in AXIN2 cause colorectal cancer with defective mismatch repair by activating beta-catenin/TCF signalling. 2000, Pubmed
Liu, Requirement for Wnt3 in vertebrate axis formation. 1999, Pubmed
Logan, The Wnt signaling pathway in development and disease. 2004, Pubmed
Luo, Wnt signaling and human diseases: what are the therapeutic implications? 2007, Pubmed
Lyuksyutova, Anterior-posterior guidance of commissural axons by Wnt-frizzled signaling. 2003, Pubmed
Majumdar, Wnt11 and Ret/Gdnf pathways cooperate in regulating ureteric branching during metanephric kidney development. 2003, Pubmed
Mao, LDL-receptor-related protein 6 is a receptor for Dickkopf proteins. 2001, Pubmed , Xenbase
Mao, Kremen proteins are Dickkopf receptors that regulate Wnt/beta-catenin signalling. 2002, Pubmed
Mao, Kremen2 modulates Dickkopf2 activity during Wnt/LRP6 signaling. 2003, Pubmed , Xenbase
Mastick, Early deletion of neuromeres in Wnt-1-/- mutant mice: evaluation by morphological and molecular markers. 1996, Pubmed
Mazieres, Wnt inhibitory factor-1 is silenced by promoter hypermethylation in human lung cancer. 2004, Pubmed
McMahon, The Wnt family of cell signalling molecules in postimplantation development of the mouse. 1992, Pubmed
McMahon, Ectopic expression of the proto-oncogene int-1 in Xenopus embryos leads to duplication of the embryonic axis. 1989, Pubmed , Xenbase
McMahon, The Wnt-1 (int-1) proto-oncogene is required for development of a large region of the mouse brain. 1990, Pubmed
Miller, The Wnts. 2002, Pubmed
Miyaoka, Increased expression of Wnt-1 in schizophrenic brains. 1999, Pubmed
Moon, WNT and beta-catenin signalling: diseases and therapies. 2004, Pubmed
Morin, Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. 1997, Pubmed
Morin, beta-catenin signaling and cancer. 1999, Pubmed
Morvan, Deletion of a single allele of the Dkk1 gene leads to an increase in bone formation and bone mass. 2006, Pubmed
Mukhopadhyay, Dkk2 plays an essential role in the corneal fate of the ocular surface epithelium. 2006, Pubmed
Mukhopadhyay, Dickkopf1 is required for embryonic head induction and limb morphogenesis in the mouse. 2001, Pubmed , Xenbase
Nakamura, Molecular cloning and characterization of Kremen, a novel kringle-containing transmembrane protein. 2001, Pubmed
Nakamura, A Wnt- and beta -catenin-dependent pathway for mammalian cardiac myogenesis. 2003, Pubmed
Nakamura, Molecular cloning and expression of human hepatocyte growth factor. 1989, Pubmed
Niehrs, Function and biological roles of the Dickkopf family of Wnt modulators. 2006, Pubmed , Xenbase
Niemann, Homozygous WNT3 mutation causes tetra-amelia in a large consanguineous family. 2004, Pubmed
Nishisho, Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. 1991, Pubmed
Nomi, Loss of mRor1 enhances the heart and skeletal abnormalities in mRor2-deficient mice: redundant and pleiotropic functions of mRor1 and mRor2 receptor tyrosine kinases. 2001, Pubmed
Nusse, Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome. 1982, Pubmed
Oishi, A novel Drosophila receptor tyrosine kinase expressed specifically in the nervous system. Unique structural features and implication in developmental signaling. 1997, Pubmed
Oishi, The receptor tyrosine kinase Ror2 is involved in non-canonical Wnt5a/JNK signalling pathway. 2003, Pubmed , Xenbase
Oishi, Spatio-temporally regulated expression of receptor tyrosine kinases, mRor1, mRor2, during mouse development: implications in development and function of the nervous system. 1999, Pubmed
Okubo, Hyperactive Wnt signaling changes the developmental potential of embryonic lung endoderm. 2004, Pubmed
Olson, Sizing up the heart: development redux in disease. 2003, Pubmed
Parr, Sexually dimorphic development of the mammalian reproductive tract requires Wnt-7a. 1998, Pubmed
Patton, Robinow syndrome. 2002, Pubmed
Pinson, An LDL-receptor-related protein mediates Wnt signalling in mice. 2000, Pubmed
Polakis, The many ways of Wnt in cancer. 2007, Pubmed
Polakis, The oncogenic activation of beta-catenin. 1999, Pubmed
Polakis, Wnt signaling and cancer. 2000, Pubmed
Reya, Wnt signalling in stem cells and cancer. 2005, Pubmed
Robitaille, Mutant frizzled-4 disrupts retinal angiogenesis in familial exudative vitreoretinopathy. 2002, Pubmed , Xenbase
Sanbe, Reengineering inducible cardiac-specific transgenesis with an attenuated myosin heavy chain promoter. 2003, Pubmed
Schlüter, Synchronization and integration of multiple hypertrophic pathways in the heart. 2004, Pubmed
Schneider, Wnt antagonism initiates cardiogenesis in Xenopus laevis. 2001, Pubmed , Xenbase
Schwabe, Ror2 knockout mouse as a model for the developmental pathology of autosomal recessive Robinow syndrome. 2004, Pubmed
Schwabe, Distinct mutations in the receptor tyrosine kinase gene ROR2 cause brachydactyly type B. 2000, Pubmed
Shu, Wnt7b regulates mesenchymal proliferation and vascular development in the lung. 2002, Pubmed
Soliman, Recessive Robinow syndrome: with emphasis on endocrine functions. 1998, Pubmed
Staal, WNT signalling and haematopoiesis: a WNT-WNT situation. 2005, Pubmed
Stark, Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4. 1994, Pubmed
Sumanas, The putative wnt receptor Xenopus frizzled-7 functions upstream of beta-catenin in vertebrate dorsoventral mesoderm patterning. 2000, Pubmed , Xenbase
Suzuki, Epigenetic inactivation of SFRP genes allows constitutive WNT signaling in colorectal cancer. 2004, Pubmed
Takada, Monounsaturated fatty acid modification of Wnt protein: its role in Wnt secretion. 2006, Pubmed , Xenbase
Takeuchi, Mouse Ror2 receptor tyrosine kinase is required for the heart development and limb formation. 2000, Pubmed
Toomes, Mutations in LRP5 or FZD4 underlie the common familial exudative vitreoretinopathy locus on chromosome 11q. 2004, Pubmed
Uematsu, Activation of the Wnt pathway in non small cell lung cancer: evidence of dishevelled overexpression. 2003, Pubmed
Vainio, Female development in mammals is regulated by Wnt-4 signalling. 1999, Pubmed
van Bokhoven, Mutation of the gene encoding the ROR2 tyrosine kinase causes autosomal recessive Robinow syndrome. 2000, Pubmed
van de Schans, Interruption of Wnt signaling attenuates the onset of pressure overload-induced cardiac hypertrophy. 2007, Pubmed
Van Raay, Wnt/frizzled signaling during vertebrate retinal development. 2004, Pubmed
Varela, The 2.4 A resolution crystal structure of boar seminal plasma PSP-I/PSP-II: a zona pellucida-binding glycoprotein heterodimer of the spermadhesin family built by a CUB domain architecture. 1997, Pubmed
Verna, A family of genes required for maintenance of cell wall integrity and for the stress response in Saccharomyces cerevisiae. 1997, Pubmed
Wang, Progressive cerebellar, auditory, and esophageal dysfunction caused by targeted disruption of the frizzled-4 gene. 2001, Pubmed
Wang, Frizzled-3 is required for the development of major fiber tracts in the rostral CNS. 2002, Pubmed
Willert, Wnt proteins are lipid-modified and can act as stem cell growth factors. 2003, Pubmed , Xenbase
Xu, Vascular development in the retina and inner ear: control by Norrin and Frizzled-4, a high-affinity ligand-receptor pair. 2004, Pubmed
Yamaguchi, A Wnt5a pathway underlies outgrowth of multiple structures in the vertebrate embryo. 1999, Pubmed
Yamashita, Prospective identification of cardiac progenitors by a novel single cell-based cardiomyocyte induction. 2005, Pubmed
Yoshikawa, Evidence that absence of Wnt-3a signaling promotes neuralization instead of paraxial mesoderm development in the mouse. 1997, Pubmed
You, Inhibition of Wnt-2-mediated signaling induces programmed cell death in non-small-cell lung cancer cells. 2004, Pubmed