misspliced mutants of LRP5 support enhanced beta-catenin-dependent signaling

Stable Identifier
R-HSA-5339711
Type
Reaction [transition]
Species
Homo sapiens
Compartment
plasma membrane
ReviewStatus
5/5
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misspliced mutants of LRP5 support enhanced beta-catenin-dependent signaling
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Frequent expression of an internally deleted LRP5 has been identified in parathyroid and breast cancers. Expression of the internally deleted LRP5 protein results in elevated levels of the active, unphosphorylated beta-catenin, enhanced expression of the both WNT-dependent reporter genes and the endogenous WNT-target gene MYC, and is required for cellular proliferation (Bjorklund et al, 2007a, b; Bjorklund et al, 2009). The in-frame internal deletion, which removes residues 666-809, arises through the aberrant use of cryptic splice sites in imperfect direct repeat sequences in exons 9 and 11 (Bjorklund et al, 2007b). This region has been shown to contain residues required for inhibition of beta-catenin activity by the negative regulator DKK1; consistent with this, expression of LRP5del666-809 is insensitive to inhibition by DKK1 (Zhang et al, 2004; Bjorklund et al, 2007b; Bjorklund et al, 2009). It has not been determined whether the LRP666-809del affects the interaction with SOST.
Literature References
PubMed ID Title Journal Year
19158955 The internally truncated LRP5 receptor presents a therapeutic target in breast cancer

Björklund, P, Akerström, G, Olsson, AK, Westin, G, Svedlund, J

PLoS ONE 2009
18044981 An LRP5 receptor with internal deletion in hyperparathyroid tumors with implications for deregulated WNT/beta-catenin signaling

Björklund, P, Akerström, G, Westin, G

PLoS Med. 2007
17047023 Accumulation of nonphosphorylated beta-catenin and c-myc in primary and uremic secondary hyperparathyroid tumors

Björklund, P, Akerström, G, Westin, G

J. Clin. Endocrinol. Metab. 2007
Participants
Input
Participates
as an event of
Normal reaction
DKK and KRM bind LRP5/6 (Homo sapiens)
Functional status

Loss of function of LRP5 del666-809 [plasma membrane]

Normal Entity
Disease Entity
Status
Disease
Name Identifier Synonyms
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
parathyroid carcinoma DOID:1540 malignant neoplasm of parathyroid gland, malignant neoplasm of the Parathyroid, parathyroid gland cancer, neoplasm of parathyroid gland, carcinoma of Parathyroid gland, Parathyroid gland neoplasm, malignant tumor of parathyroid gland (disorder), parathyroid neoplasm
breast cancer DOID:1612 malignant tumor of the breast, mammary cancer, malignant neoplasm of breast, mammary tumor, primary breast cancer, breast cancer, Ca breast - NOS, breast tumor
Authored
Rothfels, K  (2014-02-22)
Reviewed
Salahshor, S  (2014-05-12)
Woodgett, J  (2014-05-22)
Created
Rothfels, K  (2014-03-08)
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