Entry - *609899 - KRINGLE DOMAIN-CONTAINING TRANSMEMBRANE PROTEIN 2; KREMEN2 - OMIM

 
 
* 609899

KRINGLE DOMAIN-CONTAINING TRANSMEMBRANE PROTEIN 2; KREMEN2


Alternative titles; symbols

KRM2


HGNC Approved Gene Symbol: KREMEN2

Cytogenetic location: 16p13.3     Genomic coordinates (GRCh38): 16:2,964,275-2,968,380 (from NCBI)


TEXT

▼ Description

KRM1 (609898) and KRM2 are transmembrane coreceptors for DKK1 (605189), an antagonist of Wnt (see WNT1; 164820)/beta-catenin (see CTNNB1; 116806) signaling (Mao et al., 2002; Ellwanger et al., 2008).


▼ Cloning and Expression

Mao et al. (2002) cloned mouse Krm2. The Krm2 protein contains an N-terminal signal sequence, followed by a kringle domain, a WSC domain, a CUB domain, a transmembrane domain, and an intracellular C-terminal tail.


▼ Mapping

Gross (2014) mapped the KREMEN2 gene to chromosome 16p13.3 based on an alignment of the KREMEN2 sequence (GenBank AB086355) with the genomic sequence (GRCh37).

▼ Gene Function

By transfecting mouse Krm1 and Krm2 and Xenopus Dkk1 in human embryonic kidney cells and Drosophila, Mao et al. (2002) found that Krm1 and Krm2 functioned as high-affinity Dkk1 receptors that cooperated with Dkk1 to block Wnt/beta-catenin signaling.


▼ Animal Model

Ellwanger et al. (2008) found that Krm1 -/- Krm2 -/- double-knockout mice were viable and fertile. However, most Krm1 -/- Krm2 -/- mice had ectopic postaxial forelimb digits of variable size. Dkk1 +/- mice had normal limbs, but Krm1 -/- Krm2 -/- Dkk1 +/- triple-mutant mice had enhanced frequency and size of ectopic digits compared with double-knockout mice. Unlike polydactyly in the double-knockout mice, the extra digits in triple mutants originated not only from digit V, but also from the carpus. During development, the Krm proteins and Dkk1 were coexpressed in the apical ectodermal ridge (AER), attenuated Wnt signaling, and delimited the posterior boundary of the AER. Loss of Krm led to increased Wnt3 (165330)/beta-catenin signaling and AER expansion. Further analysis of mutant mice showed that the Krm proteins were required to negatively regulate bone formation, consistent with their function as Wnt inhibitors. Ellwanger et al. (2008) concluded that KRM proteins functionally interact with DKK1 as negative regulators of Wnt/beta-catenin signaling and that KRM proteins are not universally required for DKK1 function.


▼ REFERENCES

  1. Ellwanger, K., Saito, H., Clement-Lacroix, P., Maltry, N., Niedermeyer, J., Lee, W. K., Baron, R., Rawadi, G., Westphal, H., Niehrs, C. Targeted disruption of the Wnt regulator Kremen induces limb defects and high bone density. Molec. Cell. Biol. 28: 4875-4882, 2008. [PubMed: 18505822, related citations] [Full Text]

  2. Gross, M. B. Personal Communication. Baltimore, Md. 5/21/2014.

  3. Mao, B., Wu, W., Davidson, G., Marhold, J., Li, M., Mechler, B. M., Delius, H., Hoppe, D., Stannek, P., Walter, C., Glinka, A., Niehrs, C. Kremen proteins are Dickkopf receptors that regulate Wnt/beta-catenin signalling. Nature 417: 664-667, 2002. [PubMed: 12050670, related citations] [Full Text]


Contributors:
Paul J. Converse - updated : 10/16/2017
Matthew B. Gross - updated : 05/21/2014
Creation Date:
Patricia A. Hartz : 2/20/2006
Edit History:
mgross : 10/16/2017
mgross : 05/21/2014
mgross : 2/20/2006

* 609899

KRINGLE DOMAIN-CONTAINING TRANSMEMBRANE PROTEIN 2; KREMEN2


Alternative titles; symbols

KRM2


HGNC Approved Gene Symbol: KREMEN2

Cytogenetic location: 16p13.3     Genomic coordinates (GRCh38): 16:2,964,275-2,968,380 (from NCBI)


TEXT

Description

KRM1 (609898) and KRM2 are transmembrane coreceptors for DKK1 (605189), an antagonist of Wnt (see WNT1; 164820)/beta-catenin (see CTNNB1; 116806) signaling (Mao et al., 2002; Ellwanger et al., 2008).


Cloning and Expression

Mao et al. (2002) cloned mouse Krm2. The Krm2 protein contains an N-terminal signal sequence, followed by a kringle domain, a WSC domain, a CUB domain, a transmembrane domain, and an intracellular C-terminal tail.


Mapping

Gross (2014) mapped the KREMEN2 gene to chromosome 16p13.3 based on an alignment of the KREMEN2 sequence (GenBank AB086355) with the genomic sequence (GRCh37).

Gene Function

By transfecting mouse Krm1 and Krm2 and Xenopus Dkk1 in human embryonic kidney cells and Drosophila, Mao et al. (2002) found that Krm1 and Krm2 functioned as high-affinity Dkk1 receptors that cooperated with Dkk1 to block Wnt/beta-catenin signaling.


Animal Model

Ellwanger et al. (2008) found that Krm1 -/- Krm2 -/- double-knockout mice were viable and fertile. However, most Krm1 -/- Krm2 -/- mice had ectopic postaxial forelimb digits of variable size. Dkk1 +/- mice had normal limbs, but Krm1 -/- Krm2 -/- Dkk1 +/- triple-mutant mice had enhanced frequency and size of ectopic digits compared with double-knockout mice. Unlike polydactyly in the double-knockout mice, the extra digits in triple mutants originated not only from digit V, but also from the carpus. During development, the Krm proteins and Dkk1 were coexpressed in the apical ectodermal ridge (AER), attenuated Wnt signaling, and delimited the posterior boundary of the AER. Loss of Krm led to increased Wnt3 (165330)/beta-catenin signaling and AER expansion. Further analysis of mutant mice showed that the Krm proteins were required to negatively regulate bone formation, consistent with their function as Wnt inhibitors. Ellwanger et al. (2008) concluded that KRM proteins functionally interact with DKK1 as negative regulators of Wnt/beta-catenin signaling and that KRM proteins are not universally required for DKK1 function.


REFERENCES

  1. Ellwanger, K., Saito, H., Clement-Lacroix, P., Maltry, N., Niedermeyer, J., Lee, W. K., Baron, R., Rawadi, G., Westphal, H., Niehrs, C. Targeted disruption of the Wnt regulator Kremen induces limb defects and high bone density. Molec. Cell. Biol. 28: 4875-4882, 2008. [PubMed: 18505822] [Full Text: https://doi.org/10.1128/MCB.00222-08]

  2. Gross, M. B. Personal Communication. Baltimore, Md. 5/21/2014.

  3. Mao, B., Wu, W., Davidson, G., Marhold, J., Li, M., Mechler, B. M., Delius, H., Hoppe, D., Stannek, P., Walter, C., Glinka, A., Niehrs, C. Kremen proteins are Dickkopf receptors that regulate Wnt/beta-catenin signalling. Nature 417: 664-667, 2002. [PubMed: 12050670] [Full Text: https://doi.org/10.1038/nature756]


Contributors:
Paul J. Converse - updated : 10/16/2017
Matthew B. Gross - updated : 05/21/2014

Creation Date:
Patricia A. Hartz : 2/20/2006

Edit History:
mgross : 10/16/2017
mgross : 05/21/2014
mgross : 2/20/2006



NOTE: OMIM is intended for use primarily by physicians and other professionals concerned with genetic disorders, by genetics researchers, and by advanced students in science and medicine. While the OMIM database is open to the public, users seeking information about a personal medical or genetic condition are urged to consult with a qualified physician for diagnosis and for answers to personal questions.
OMIM® and Online Mendelian Inheritance in Man® are registered trademarks of the Johns Hopkins University.
Copyright® 1966-2024 Johns Hopkins University.

NOTE: OMIM is intended for use primarily by physicians and other professionals concerned with genetic disorders, by genetics researchers, and by advanced students in science and medicine. While the OMIM database is open to the public, users seeking information about a personal medical or genetic condition are urged to consult with a qualified physician for diagnosis and for answers to personal questions.
OMIM® and Online Mendelian Inheritance in Man® are registered trademarks of the Johns Hopkins University.
Copyright® 1966-2024 Johns Hopkins University.
Printed: April 25, 2024