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Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors
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Inhibitor-1 and -2 of PP2A have preference between PP2A complexes.
Hirotsugu Hino1, Kaori Takaki1, Satoru Mochida2
1Priority Organization for Innovation and Excellence, Kumamoto University, Honjo-Kyoyotou, 2-2-1 Honjo, Chuo-ku, Kumamoto City, Kumamoto 860-0811, Japan.
Biochemical and Biophysical Research Communications
|October 10, 2015
Summary
Two protein inhibitors, I1(PP2A) and I2(PP2A), differentially regulate Protein Phosphatase 2A (PP2A) complexes. These inhibitors exhibit B-subunit specificity, suggesting distinct in vivo control mechanisms for PP2A functions.
Area of Science:
- Biochemistry
- Molecular Biology
- Cell Biology
Background:
- Protein Phosphatase 2A (PP2A) is a crucial enzyme involved in numerous cellular processes.
- PP2A functions through diverse complexes formed with various regulatory B subunits, each conferring specific substrate targeting and functions.
- The precise regulation of individual PP2A complex activities remains incompletely understood.
Purpose of the Study:
- To investigate the differential inhibitory effects of two proteinous PP2A inhibitors, I1(PP2A) and I2(PP2A), on distinct PP2A complexes.
- To determine the B-subunit specificity of I1(PP2A) and I2(PP2A) interactions within PP2A complexes.
- To provide evidence supporting the hypothesis of individual regulation for PP2A complexes in vivo.
Main Methods:
- Utilized immunoprecipitation assays.
- Employed Xenopus egg extracts for experimental system.
- Analyzed interactions between PP2A inhibitors and various B subunits (B56γ, B″/PR48).
Main Results:
- Demonstrated unequal enzyme inhibition of different PP2A forms by I1(PP2A) and I2(PP2A).
- Showed that I1(PP2A) specifically binds to the B″/PR48 subunit.
- Revealed that I2(PP2A) interacts with both B56γ and B″/PR48 subunits among the analyzed B subunits.
Conclusions:
- I1(PP2A) and I2(PP2A) exhibit specificity towards distinct B subunits of PP2A.
- These findings support the model where PP2A complexes, despite sharing a common catalytic subunit, are individually regulated.
- This differential regulation allows for distinct functions of PP2A complexes in vivo.
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