An six-amino acid motif in the α3 domain of MICA is the cancer therapeutic target to inhibit shedding

Xuanjun Wang; Ashley D. Lundgren; Pragya Singh; David R. Goodlett; Stephen R. Plymate; Jennifer D. Wu

doi:10.1016/j.bbrc.2009.07.062

An six-amino acid motif in the α3 domain of MICA is the cancer therapeutic target to inhibit shedding

Xuanjun Wang, Ashley D. Lundgren, Pragya Singh, David R. Goodlett, Stephen R. Plymate, Jennifer D. Wu^*

^*Corresponding author for this work

Urology

Research output: Contribution to journal › Article › peer-review

34 Scopus citations

Abstract

Expression of the MHC class I chain related molecules A and B (MICA/B) on tumor cell surface can signal the immune receptor NKG2D for tumor immune destruction. However, MIC was found to be shed by tumors in cancer patients, which negatively regulates host immunity and promotes tumor immune evasion and progression. The mechanisms by which tumors shed MIC are not well understood although diverse groups of enzymes are suggested to be involved. The functional complexity of these enzymes makes them unfeasible therapeutic targets for inhibiting MIC shedding. Here we identified an six-amino acid (6-aa) motif in the α3 domain of MIC that is critical for the interaction of MIC with ERp5 to enable shedding. Mutations in this motif prevented MIC shedding but did not interfere with NKG2D-mediated recognition of MIC. Our study suggests that the 6-aa motif is a feasible target to inhibit MIC shedding for cancer therapy.

Original language	English (US)
Pages (from-to)	476-481
Number of pages	6
Journal	Biochemical and Biophysical Research Communications
Volume	387
Issue number	3
DOIs	https://doi.org/10.1016/j.bbrc.2009.07.062
State	Published - Sep 25 2009

Keywords

Cancer therapeutic target
MHC class I chain related molecule (MIC)
NKG2D
Protein disulfide isomerase ERp5
Tumor immunity
Tumor shedding

ASJC Scopus subject areas

Molecular Biology
Biophysics
Biochemistry
Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bbrc.2009.07.062

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title = "An six-amino acid motif in the α3 domain of MICA is the cancer therapeutic target to inhibit shedding",

abstract = "Expression of the MHC class I chain related molecules A and B (MICA/B) on tumor cell surface can signal the immune receptor NKG2D for tumor immune destruction. However, MIC was found to be shed by tumors in cancer patients, which negatively regulates host immunity and promotes tumor immune evasion and progression. The mechanisms by which tumors shed MIC are not well understood although diverse groups of enzymes are suggested to be involved. The functional complexity of these enzymes makes them unfeasible therapeutic targets for inhibiting MIC shedding. Here we identified an six-amino acid (6-aa) motif in the α3 domain of MIC that is critical for the interaction of MIC with ERp5 to enable shedding. Mutations in this motif prevented MIC shedding but did not interfere with NKG2D-mediated recognition of MIC. Our study suggests that the 6-aa motif is a feasible target to inhibit MIC shedding for cancer therapy.",

keywords = "Cancer therapeutic target, MHC class I chain related molecule (MIC), NKG2D, Protein disulfide isomerase ERp5, Tumor immunity, Tumor shedding",

author = "Xuanjun Wang and Lundgren, {Ashley D.} and Pragya Singh and Goodlett, {David R.} and Plymate, {Stephen R.} and Wu, {Jennifer D.}",

note = "Funding Information: This work was supported by DOD-USMRC New Investigators Award W81XWH-04-1-0577, DOD-USMRC IDEA Development Award W81XWH-06-1-0014, NW Prostate SPORE Program, NIH Research Grant R33CA099139, and NIH Temin Award 1K01CA116002. ",

year = "2009",

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doi = "10.1016/j.bbrc.2009.07.062",

language = "English (US)",

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AU - Wang, Xuanjun

AU - Lundgren, Ashley D.

AU - Singh, Pragya

AU - Goodlett, David R.

AU - Plymate, Stephen R.

AU - Wu, Jennifer D.

N1 - Funding Information: This work was supported by DOD-USMRC New Investigators Award W81XWH-04-1-0577, DOD-USMRC IDEA Development Award W81XWH-06-1-0014, NW Prostate SPORE Program, NIH Research Grant R33CA099139, and NIH Temin Award 1K01CA116002.

PY - 2009/9/25

Y1 - 2009/9/25

N2 - Expression of the MHC class I chain related molecules A and B (MICA/B) on tumor cell surface can signal the immune receptor NKG2D for tumor immune destruction. However, MIC was found to be shed by tumors in cancer patients, which negatively regulates host immunity and promotes tumor immune evasion and progression. The mechanisms by which tumors shed MIC are not well understood although diverse groups of enzymes are suggested to be involved. The functional complexity of these enzymes makes them unfeasible therapeutic targets for inhibiting MIC shedding. Here we identified an six-amino acid (6-aa) motif in the α3 domain of MIC that is critical for the interaction of MIC with ERp5 to enable shedding. Mutations in this motif prevented MIC shedding but did not interfere with NKG2D-mediated recognition of MIC. Our study suggests that the 6-aa motif is a feasible target to inhibit MIC shedding for cancer therapy.

AB - Expression of the MHC class I chain related molecules A and B (MICA/B) on tumor cell surface can signal the immune receptor NKG2D for tumor immune destruction. However, MIC was found to be shed by tumors in cancer patients, which negatively regulates host immunity and promotes tumor immune evasion and progression. The mechanisms by which tumors shed MIC are not well understood although diverse groups of enzymes are suggested to be involved. The functional complexity of these enzymes makes them unfeasible therapeutic targets for inhibiting MIC shedding. Here we identified an six-amino acid (6-aa) motif in the α3 domain of MIC that is critical for the interaction of MIC with ERp5 to enable shedding. Mutations in this motif prevented MIC shedding but did not interfere with NKG2D-mediated recognition of MIC. Our study suggests that the 6-aa motif is a feasible target to inhibit MIC shedding for cancer therapy.

KW - Cancer therapeutic target

KW - MHC class I chain related molecule (MIC)

KW - NKG2D

KW - Protein disulfide isomerase ERp5

KW - Tumor immunity

KW - Tumor shedding

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An six-amino acid motif in the α3 domain of MICA is the cancer therapeutic target to inhibit shedding

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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