Proteomics

Dataset Information

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RNA-binding proteins associating with the 3’UTR of the ATP6V1A transcript in SIRT1 knock-down cells


ABSTRACT: Insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2) binds various RNA transcripts and functions as a tumor promoter, although little is known regarding the mechanisms that regulate its roles in RNA metabolism (1-3). Here we find that IGF2BP2 binds to the 3’ untranslated region of the transcript encoding ATP6V1A, a major catalytic subunit of the vacuolar ATPase (v-ATPase), and regulates its degradation in a lysine acetylation and SIRT1-dependent manner. We show that the regulation of IGF2BP2 is significantly compromised in breast cancer cells where SIRT1 expression is low or knocked-down. Reduced SIRT1 expression leads to an increase in acetylated IGF2BP2, which enables IGF2BP2 to recruit the XRN2 nuclease to the ATP6V1A transcript, resulting in its degradation and a reduction in the expression of functional v-ATPase complexes. This impairs lysosomal activity and produces a cellular secretome consisting of increased numbers of exosomes enriched in ubiquitinated protein cargo and soluble hydrolases including cathepsins, which combine to promote tumor progression and invasiveness. Collectively, these findings describe a previously unrecognized role for IGF2BP2 in mediating the degradation of an mRNA transcript essential for lysosomal function and highlight how its sirtuin-regulated acetylation state can have significant biological and disease consequences.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Breast, Breast Cancer Cell Line

DISEASE(S): Breast Cancer

SUBMITTER: Elena Panizza  

LAB HEAD: Richard A. Cerione

PROVIDER: PXD028114 | Pride | 2023-03-10

REPOSITORIES: Pride

Dataset's files

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Action DRS
Arash10400399_Band1_60kD-_2_.msf Msf
Arash10400399_Band1_60kD-_2_.pdResult Other
Arash10400399_Band1_60kD.raw Raw
Arash10400399_Band1_60kD.xlsx Xlsx
Arash10400399_Band2_85kD-_1_.msf Msf
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Publications

IGF2BP2 promotes cancer progression by degrading the RNA transcript encoding a v-ATPase subunit.

Latifkar Arash A   Wang Fangyu F   Mullmann James J JJ   Panizza Elena E   Fernandez Irma R IR   Ling Lu L   Miller Andrew D AD   Fischbach Claudia C   Weiss Robert S RS   Lin Hening H   Cerione Richard A RA   Antonyak Marc A MA  

Proceedings of the National Academy of Sciences of the United States of America 20221102 45


IGF2BP2 binds to a number of RNA transcripts and has been suggested to function as a tumor promoter, although little is known regarding the mechanisms that regulate its roles in RNA metabolism. Here we demonstrate that IGF2BP2 binds to the 3' untranslated region of the transcript encoding ATP6V1A, a catalytic subunit of the vacuolar ATPase (v-ATPase), and serves as a substrate for the NAD<sup>+</sup>-dependent deacetylase SIRT1, which regulates how IGF2BP2 affects the stability of the ATP6V1A tr  ...[more]

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