TY - JOUR
T1 - Dominant-negative effect of truncated mannose 6-phosphate/insulin-like growth factor II receptor species in cancer
AU - Kreiling, Jodi L.
AU - Montgomery, Michelle A.
AU - Wheeler, Joseph R.
AU - Kopanic, Jennifer L.
AU - Connelly, Christopher M.
AU - Zavorka, Megan E.
AU - Allison, Jenna L.
AU - MacDonald, Richard G.
PY - 2012/8
Y1 - 2012/8
N2 - Oligomerization of the mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGF2R) is important for optimal ligand binding and internalization. M6P/IGF2R is a tumor suppressor gene that exhibits loss of heterozygosity and is mutated in several cancers. We tested the potential dominant-negative effects of two cancer-associated mutations that truncate M6P/IGF2R in ectodomain repeats 9 and 14. Our hypothesis was that co-expression of the truncated receptors with the wild-type/endogenous full-length M6P/IGF2R would interfere with M6P/IGF2R function by heterodimer interference. Immunoprecipitation confirmed formation of heterodimeric complexes between full-length M6P/IGF2Rs and the truncated receptors, termed Rep9F and Rep14F. Remarkably, increasing expression of either Rep9F or Rep14F provoked decreased levels of full-length M6P/IGF2Rs in both cell lysates and plasma membranes, indicating a dominant-negative effect on receptor availability. Loss of full-length M6P/IGF2R was not due to increased proteasomal or lysosomal degradation, but instead arose from increased proteolytic cleavage of cell-surface M6P/IGF2Rs, resulting in ectodomain release, by a mechanism that was inhibited by metal ion chelators. These data suggest that M6P/IGF2R truncation mutants may contribute to the cancer phenotype by decreasing the availability of full-length M6P/IGF2Rs to perform tumor-suppressive functions such as binding/internalization of receptor ligands such as insulin-like growth factor II. Structured digital abstract with by (View Interaction:,) with by (View Interaction:,) Oligomerization of the mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGF2R) is important for optimal IGF-II binding, internalization, and degradation. Increasing expression of Rep9F or Rep14F, two cancer-associated M6P/IGF2R mutations that truncate the receptor in ectodomain repeats 9 and 14 decreased levels of full-length M6P/IGF2Rs. The effect was due to proteolytic cleavage resulting in ectodomain release and was inhibited by zinc chelators
AB - Oligomerization of the mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGF2R) is important for optimal ligand binding and internalization. M6P/IGF2R is a tumor suppressor gene that exhibits loss of heterozygosity and is mutated in several cancers. We tested the potential dominant-negative effects of two cancer-associated mutations that truncate M6P/IGF2R in ectodomain repeats 9 and 14. Our hypothesis was that co-expression of the truncated receptors with the wild-type/endogenous full-length M6P/IGF2R would interfere with M6P/IGF2R function by heterodimer interference. Immunoprecipitation confirmed formation of heterodimeric complexes between full-length M6P/IGF2Rs and the truncated receptors, termed Rep9F and Rep14F. Remarkably, increasing expression of either Rep9F or Rep14F provoked decreased levels of full-length M6P/IGF2Rs in both cell lysates and plasma membranes, indicating a dominant-negative effect on receptor availability. Loss of full-length M6P/IGF2R was not due to increased proteasomal or lysosomal degradation, but instead arose from increased proteolytic cleavage of cell-surface M6P/IGF2Rs, resulting in ectodomain release, by a mechanism that was inhibited by metal ion chelators. These data suggest that M6P/IGF2R truncation mutants may contribute to the cancer phenotype by decreasing the availability of full-length M6P/IGF2Rs to perform tumor-suppressive functions such as binding/internalization of receptor ligands such as insulin-like growth factor II. Structured digital abstract with by (View Interaction:,) with by (View Interaction:,) Oligomerization of the mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGF2R) is important for optimal IGF-II binding, internalization, and degradation. Increasing expression of Rep9F or Rep14F, two cancer-associated M6P/IGF2R mutations that truncate the receptor in ectodomain repeats 9 and 14 decreased levels of full-length M6P/IGF2Rs. The effect was due to proteolytic cleavage resulting in ectodomain release and was inhibited by zinc chelators
KW - dimerization
KW - dominant negative
KW - ectodomain shedding
KW - mannose 6-phosphate receptor
KW - truncation mutants
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U2 - 10.1111/j.1742-4658.2012.08652.x
DO - 10.1111/j.1742-4658.2012.08652.x
M3 - Article
C2 - 22681933
AN - SCOPUS:84863840659
SN - 1742-464X
VL - 279
SP - 2695
EP - 2713
JO - FEBS Journal
JF - FEBS Journal
IS - 15
ER -