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PP2 (kinase inhibitor)

PP2 is a substance that has frequently been used in cancer research as a "selective" inhibitor for Src-family kinases. It strongly inhibits the kinases Lck (IC50=4 nM), Fyn (5 nM) and Hck (5 nM), shows weaker inhibition of epidermal growth factor receptor (480 nM) and practically no inhibition of ZAP-70 (100 μM) and JAK2 (50 μM).[1][2][3][4] Despite its extensive use as a Src-selective inhibitor, recent research has shown that PP2 is non-selective and inhibits many other kinases with similar affinities.[5]

Structure

PP2A is a heterotrimeric enzyme composed of three types of subunits:

  • Catalytic subunit (C subunit): performs the dephosphorylation.
  • Scaffold subunit (A subunit): acts as a structural platform.
  • Regulatory subunit (B subunit): confers substrate specificity and subcellular localization.

The diversity of the B subunit family allows PP2A to form multiple holoenzymes with distinct functions, enabling it to regulate numerous cellular processes with high specificity.[6]

Function and mechanism

The central mechanisms in the regulation of most cellular processes include protein phosphorylation and dephosphorylation. PP2 enzymes specifically target proteins that are phosphorylated on serine and threonine residues.[7] The dephosphorylation reaction typically requires water molecules and is catalyzed by a conserved active site in the PP2 enzyme.

The primary function of PP2 is to reverse the actions of kinases, which add phosphate groups to proteins. By removing phosphate groups, PP2 modulates the activity, location, and interaction of the target proteins, thereby controlling various aspects of cell behavior.

Biological significance

Due to its role in controlling phosphorylation status, PP2A is implicated in various physiological and pathological conditions:

  • Cancer: PP2A acts as a tumor suppressor. Its inhibition or mutation is associated with multiple cancers, including prostate, breast, lung, and leukemia.[8]
  • Neurodegeneration: abnormal PP2A activity has been linked to Alzheimer's disease due to dysregulated tau protein phosphorylation.[9]

References

  1. ^ Hanke, JH; Gardner, JP; Dow, RL; Changelian, PS; Brissette, WH; Weringer, EJ; Pollok, BA; Connelly, PA (1996). "Discovery of a novel, potent, and Src family-selective tyrosine kinase inhibitor. Study of Lck- and FynT-dependent T cell activation". The Journal of Biological Chemistry. 271 (2): 695–701. doi:10.1074/jbc.271.2.695. PMID 8557675.
  2. ^ Chen, JK; Capdevila, J; Harris, RC (2000). "Overexpression of C-terminal Src kinase blocks 14, 15-epoxyeicosatrienoic acid-induced tyrosine phosphorylation and mitogenesis". The Journal of Biological Chemistry. 275 (18): 13789–92. doi:10.1074/jbc.275.18.13789. PMID 10788500.
  3. ^ Yoshizumi, M; Abe, J; Haendeler, J; Huang, Q; Berk, BC (2000). "Src and Cas mediate JNK activation but not ERK1/2 and p38 kinases by reactive oxygen species". The Journal of Biological Chemistry. 275 (16): 11706–12. doi:10.1074/jbc.275.16.11706. PMID 10766791.
  4. ^ Carlomagno, F; Vitagliano, D; Guida, T; Basolo, F; Castellone, MD; Melillo, RM; Fusco, A; Santoro, M (2003). "Efficient inhibition of RET/papillary thyroid carcinoma oncogenic kinases by 4-amino-5-(4-chloro-phenyl)-7-(t-butyl)pyrazolo3,4-dpyrimidine (PP2)". The Journal of Clinical Endocrinology and Metabolism. 88 (4): 1897–902. doi:10.1210/jc.2002-021278. PMID 12679489.
  5. ^ Brandvold, KR; Steffey, ME; Fox, CC; Soellner, MB (2012). "Development of a Highly Selective c-Src Kinase Inhibitor". ACS Chemical Biology. ASAP (8): 1393–1398. doi:10.1021/cb300172e. PMC 3423592. PMID 22594480.
  6. ^ Sents, Ward; Ivanova, Elitsa; Lambrecht, Caroline; Haesen, Dorien; Janssens, Veerle (2013). "The biogenesis of active protein phosphatase 2A holoenzymes: a tightly regulated process creating phosphatase specificity". The FEBS Journal. 280 (2): 644–661. doi:10.1111/j.1742-4658.2012.08579.x. ISSN 1742-4658. PMID 22443683.
  7. ^ Ugi, Satoshi; Imamura, Takeshi; Maegawa, Hiroshi; Egawa, Katsuya; Yoshizaki, Takeshi; Shi, Kun; Obata, Toshiyuki; Ebina, Yousuke; Kashiwagi, Atsunori; Olefsky, Jerrold M. (2004-10-01). "Protein Phosphatase 2A Negatively Regulates Insulin's Metabolic Signaling Pathway by Inhibiting Akt (Protein Kinase B) Activity in 3T3-L1 Adipocytes". Molecular and Cellular Biology. 24 (19): 8778–8789. doi:10.1128/MCB.24.19.8778-8789.2004. ISSN 1098-5549. PMC 516764. PMID 15367694.
  8. ^ Pandey, P; Seshacharyulu, P; Das, S; Rachagani, S; Ponnusamy, M P; Yan, Y; Johansson, S L; Datta, K; Fong Lin, M; Batra, S K (June 2013). "Impaired expression of protein phosphatase 2A subunits enhances metastatic potential of human prostate cancer cells through activation of AKT pathway". British Journal of Cancer. 108 (12): 2590–2600. doi:10.1038/bjc.2013.160. ISSN 0007-0920. PMC 3694226. PMID 23598299.
  9. ^ McKenzie-Nickson, Simon; Chan, Jacky; Perez, Keyla; Hung, Lin W.; Cheng, Lesley; Sedjahtera, Amelia; Gunawan, Lydia; Adlard, Paul A.; Hayne, David J.; McInnes, Lachlan E.; Donnelly, Paul S.; Finkelstein, David I.; Hill, Andrew F.; Barnham, Kevin J. (2018-11-21). "Modulating Protein Phosphatase 2A Rescues Disease Phenotype in Neurodegenerative Tauopathies". ACS Chemical Neuroscience. 9 (11): 2731–2740. doi:10.1021/acschemneuro.8b00161. ISSN 1948-7193.