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Highlights d SMAPs bind at an intersubunit pocket defined by all three PP2A subunits d DT-061 (SMAP) binding results in selective stabilization of PP2A-B56a heterotrimers d Stabilization of B56a heterotrimers biases PP2A toward substrates such as c-Myc d Accumulation of methylated, B56a heterotrimers, is a potential clinical biomarker

Protein phosphatase 2A (PP2A) is a major serine/threonine phosphatase that regulates many cellular processes. Given the central role of PP2A in regulating diverse biological functions and its dysregulation in many diseases, including cancer, PP2A directed therapeutics have become of great interest. The main approaches leveraged thus far can be categorized as follows: 1) inhibiting endogenous inhibitors of PP2A, 2) targeted disruption of post translational modifications on PP2A subunits, or 3) direct targeting of PP2A. Additional insight into the structural, molecular, and biological framework driving the efficacy of these therapeutic strategies will provide a foundation for the refinement and development of novel and clinically tractable PP2A targeted therapies.

Kinase inhibitor resistance constitutes a major unresolved clinical challenge in cancer. Furthermore, the role of serine/threonine phosphatase deregulation as a potential cause for resistance to kinase inhibitors has not been thoroughly addressed. We characterize protein phosphatase 2A (PP2A) activity as a global determinant of KRAS-mutant lung cancer cell resistance across a library of >200 kinase inhibitors. The results show that PP2A activity modulation alters cancer cell sensitivities to a large number of kinase inhibitors. Specifically, PP2A inhibition ablated mitogen-activated protein kinase kinase (MEK) inhibitor response through the collateral activation of AKT/mammalian target of rapamycin (mTOR) signaling. Combination of mTOR and MEK inhibitors induced cytotoxicity in PP2A-inhibited cells, but even this drug combination could not abrogate MYC up-regulation in PP2A-inhibited cells. Treatment with an orally bioavailable small-molecule activator of PP2A DT-061, in combination with the MEK inhibitor AZD6244, resulted in suppression of both p-AKT and MYC, as well as tumor regression in two KRAS-driven lung cancer mouse models. DT-061 therapy also abrogated MYC-driven tumorigenesis. These data demonstrate that PP2A deregulation drives MEK inhibitor resistance in KRAS-mutant cells. These results emphasize the need for better understanding of phosphatases as key modulators of cancer therapy responses.

on behalf of the author G.N. have filed patents covering composition of matter on the small molecules disclosed herein for the treatment of human cancer and other diseases and for methods of use for using these small molecule PP2A activators. RAPPTA Therapeutics LLC has licensed this intellectual property for the clinical and commercial development of this series of small molecule PP2A activators. The author G.N. has an ownership interest in RAPPTA Therapeutics LLC.

The remodeling process can cause myocardial rupture, lead to LV dilation and ultimately cause decreased functional reserve and congestive heart failure. 1 We have previously suggested that inflammation plays a critical role in post-MI LV remodeling 2 but not infarct size. Increased WBC count is linked to increased LV size in patients with MI 3,4 and inflammation most likely associates with unfavorable outcomes by increasing the infarct size or altering ventricular remodeling. 5 Direct inhibition of WBC infiltration through the administration of an antibody to CD11b failed to reduce infarct size; however, inhibition of WBC infiltration remains a potential target to optimizing cardiac remodeling post-MI.Chemokines play an important role in the myocardial healing after MI. 6,7 Earlier data demonstrated that blocking CC chemokines is helpful in the prevention of post ischemic Original

The serine/threonine Protein Phosphatase 2A (PP2A) functions as a tumor suppressor by negatively regulating multiple oncogenic signaling pathways. The canonical PP2A holoenzyme is comprised of a scaffolding subunit (PP2A Aα/β), which serves as the platform for binding of both the catalytic C subunit and one regulatory B subunit. Somatic heterozygous missense mutations in PPP2R1A, the gene encoding the PP2A Aα scaffolding subunit, have been identified across multiple cancer types, but the effects of the most commonly mutated residue, Arg-183, on PP2A function have yet to be fully elucidated. In this study, we used a series of cellular and in vivo models and discovered that the most frequent Aα R183W mutation formed alternative holoenzymes by binding of different PP2A regulatory subunits compared to wild type Aα, Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Edited by Wolfgang Peti Protein phosphatase 2A (PP2A) represses many oncogenic signaling pathways and is an important tumor suppressor. PP2A comprises three distinct subunits and forms through a highly regulated biogenesis process, with the scaffolding A subunit existing as two highly related isoforms, A␣ and A␤. PP2A's tumor-suppressive functions have been intensely studied, and PP2A inactivation has been shown to be a prerequisite for tumor formation. Interestingly, although partial loss of the A␣ isoform is growth promoting, complete A␣ loss has no transformative properties. Additionally, in cancer patients, A␣ is found to be inactivated in a haploinsufficient manner. Using both cellular and in vivo systems, colorectal and endometrial cancer cell lines, and biochemical and cellular assays, here we examined why the complete loss of A␣ does not promote tumorigenesis. CRISPR/ Cas9-mediated homozygous A␣ deletion resulted in decreased colony formation and tumor growth across multiple cell lines. Protein expression analysis of PP2A family members revealed that the A␣ deletion markedly up-regulates A␤ protein expression by increasing A␤ protein stability. A␤ knockdown in control and A␣ knockout cell lines indicated that A␤ is necessary for cell survival in the A␣ knockout cells. In the setting of A␣ deficiency, co-immunoprecipitation analysis revealed increased binding of specific PP2A regulatory subunits to A␤, and knockdown of these regulatory subunits restored colony-forming ability. Taken together, our results uncover a mechanism by which PP2A A␣ regulates A␤ protein stability and activity and suggests why homozygous loss of A␣ is rarely seen in cancer patients.