The PP1 binding code: a molecular‐lego strategy that governs specificity

Heroes, Ewald; Lesage, Bart; Görnemann, Janina; Beullens, Monique; Meervelt, Luc Van; Bollen, Mathieu

doi:10.1111/j.1742-4658.2012.08547.x

Cited by 276 publications

(354 citation statements)

References 55 publications

(123 reference statements)

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“…Accordingly, substrate specificity of Ser/Thr phosphatases is secured mainly by a wide array of regulators. Indeed, evidence supports that the catalytic activity and substrate specificity of PP1 are also determined by diverse physically interacting regulators (58,59). It has been reported that PP1 has more than 50 known regulatory proteins, although more regulators are expected to be identified (25).…”

Section: Fig 10 Legend (Continued)mentioning

confidence: 94%

Steady-State Levels of Phosphorylated Mitogen-Activated Protein Kinase Kinase 1/2 Determined by Mortalin/HSPA9 and Protein Phosphatase 1 Alpha in KRAS and BRAF Tumor Cells

Hong

Park

2017

Molecular and Cellular Biology

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Although deregulation of MEK/extracellular signal-regulated kinase (ERK) activity is a key feature in cancer, high-magnitude MEK/ERK activity can paradoxically induce growth inhibition. Therefore, additional mechanisms may exist to modulate MEK/ERK activity in favor of tumor cell proliferation. We previously reported that mortalin/HSPA9 can facilitate proliferation of certain KRAS and BRAF tumor cells by modulating MEK/ERK activity. In this study, we demonstrated that mortalin can regulate MEK/ERK activity via protein phosphatase 1␣ (PP1␣). We found that PP1␣ inhibition increases steady-state levels of phosphorylated MEK1/2 in various tumor cells expressing B-Raf V600E or K-Ras G12C/D . Intriguingly, coimmunoprecipitation and in vitro binding assays revealed that mortalin facilitates PP1␣-mediated MEK1/2 dephosphorylation by promoting PP1␣-MEK1/2 interaction in an ATP-sensitive manner. The region spanning Val482 to Glu491 in the substrate-binding cavity and the substrate lid of mortalin were necessary for these physical interactions, which is consistent with conventional heat shock protein 70 (HSP70)-client interaction mechanisms. Nevertheless, mortalin depletion did not affect cellular PP1␣ levels or its regulatory phosphorylation, suggesting a nonconventional role for mortalin in promoting PP1␣-MEK1/2 interaction. Of note, PP1␣ was upregulated in human melanoma and pancreatic cancer biopsy specimens in correlation with mortalin upregulation. PP1␣ may therefore have a role in tumorigenesis in concert with mortalin, which affects MEK/ERK activity in tumor cells. KEYWORDS MEK1/2, ERK1/2, protein phosphatase 1, heat shock protein, mortalin T he Raf/MEK/extracellular signal-regulated kinase (ERK) pathway is a highly specific three-layer kinase cascade that consists of the Ser/Thr kinases, Raf (i.e., A-, B-, and C-Raf), the highly homologous dual-specificity kinases MEK1 and MEK2 (collectively referred to as MEK1/2), and the ubiquitously expressed Ser/Thr kinases ERK1/2 (1). Upon activation, Raf phosphorylates two Ser residues in the activation segment of MEK1/2, which in turn activate ERK1/2 by sequentially phosphorylating Tyr and Thr in their activation loop (2). ERK1/2 then activate/inactivate various targets, including transcription factors, other kinases, phosphatases, cytoskeletal proteins, scaffolds, receptors, and signaling components (1). The Raf/MEK/ERK pathway has pivotal roles in regulating cell survival, cell cycle progression, and differentiation (3), and its deregulation often leads to the onset of cancer, including malignancies of skin, thyroid, pancreas, and colon, wherein mutations in BRAF and its upstream activator, RAS, are prevalent (4).Diverse physiological outputs of Raf/MEK/ERK signaling are determined by the duration and strength of signals, physical interactions with specific scaffolds, subcellular compartmentalization, cross talk with other signaling pathways, and distinct functions

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Section: Fig 10 Legend (Continued)mentioning

confidence: 94%

Steady-State Levels of Phosphorylated Mitogen-Activated Protein Kinase Kinase 1/2 Determined by Mortalin/HSPA9 and Protein Phosphatase 1 Alpha in KRAS and BRAF Tumor Cells

Hong

Park

2017

Molecular and Cellular Biology

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“…One of the cell-cycle-regulating enzymes is the serine/threonine protein phosphatase-1 (PP1) a ubiquitously expressed and conserved member of the phosphoprotein phosphatase (PPP) superfamily (Heroes et al, 2013). PP1 forms heterodimeric or heterotrimeric complexes with >200 PP1-interacting proteins (PIPs), which function as substrate-targeting or -specifying subunits and activity regulators.…”

Section: Introductionmentioning

confidence: 99%

The selective inhibition of protein phosphatase-1 results in mitotic catastrophe and impaired tumor growth

Winkler

Munter

Dessel

et al. 2015

Journal of Cell Science

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The serine/threonine protein phosphatase-1 (PP1) complex is a key regulator of the cell cycle. However, the redundancy of PP1 isoforms and the lack of specific inhibitors have hampered studies on the global role of PP1 in cell cycle progression in vertebrates. Here, we show that the overexpression of nuclear inhibitor of PP1 (NIPP1; also known as PPP1R8) in HeLa cells culminated in a prometaphase arrest, associated with severe spindle-formation and chromosome-congression defects. In addition, the spindle assembly checkpoint was activated and checkpoint silencing was hampered. Eventually, most cells either died by apoptosis or formed binucleated cells. The NIPP1-induced mitotic arrest could be explained by the inhibition of PP1 that was titrated away from other mitotic PP1 interactors. Consistent with this notion, the mitoticarrest phenotype could be rescued by the overexpression of PP1 or the inhibition of the Aurora B kinase, which acts antagonistically to PP1. Finally, we demonstrate that the overexpression of NIPP1 also hampered colony formation and tumor growth in xenograft assays in a PP1-dependent manner. Our data show that the selective inhibition of PP1 can be used to induce cancer cell death through mitotic catastrophe.

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“…As discussed above, in large part, the catalytic subunit of PP1 is regulated by recruiting it to specific proteins at precise times. These proteins have docking sites for PP1 with a core consensus motif of (R/K-V-X-F), (F-x-x-R/K-x-R/K), or (RRVTW) (Bollen et al 2010;Heroes et al 2013). In addition, there is a global inhibition of PP1 activity as cells enter mitosis because cyclin B -Cdk phosphorylates the catalytic subunit of PP1 at an inhibitory site on its carboxyl terminus ).…”

Section: Inhibiting Protein Phosphatasesmentioning

confidence: 99%

The Biochemistry of Mitosis

Wieser

Pines

2015

Cold Spring Harb Perspect Biol

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In this article, we will discuss the biochemistry of mitosis in eukaryotic cells. We will focus on conserved principles that, importantly, are adapted to the biology of the organism. It is vital to bear in mind that the structural requirements for division in a rapidly dividing syncytial Drosophila embryo, for example, are markedly different from those in a unicellular yeast cell. Nevertheless, division in both systems is driven by conserved modules of antagonistic protein kinases and phosphatases, underpinned by ubiquitin-mediated proteolysis, which create molecular switches to drive each stage of division forward. These conserved control modules combine with the self-organizing properties of the subcellular architecture to meet the specific needs of the cell. Our discussion will draw on discoveries in several model systems that have been important in the long history of research on mitosis, and we will try to point out those principles that appear to apply to all cells, compared with those in which the biochemistry has been specifically adapted in a particular organism.

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The PP1 binding code: a molecular‐lego strategy that governs specificity

Cited by 276 publications

References 55 publications

Steady-State Levels of Phosphorylated Mitogen-Activated Protein Kinase Kinase 1/2 Determined by Mortalin/HSPA9 and Protein Phosphatase 1 Alpha in KRAS and BRAF Tumor Cells

Steady-State Levels of Phosphorylated Mitogen-Activated Protein Kinase Kinase 1/2 Determined by Mortalin/HSPA9 and Protein Phosphatase 1 Alpha in KRAS and BRAF Tumor Cells

The selective inhibition of protein phosphatase-1 results in mitotic catastrophe and impaired tumor growth

The Biochemistry of Mitosis

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