Mechanisms of site-specific dephosphorylation and kinase opposition imposed by PP2A regulatory subunits

Research output: Contribution to journal › Journal article › Research › peer-review

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Mechanisms of site-specific dephosphorylation and kinase opposition imposed by PP2A regulatory subunits. / Kruse, Thomas; Gnosa, Sebastian Peter; Nasa, Isha; Garvanska, Dimitriya Hristoforova; Hein, Jamin B.; Nguyen, Hieu; Samsøe-Petersen, Jacob; Lopez-Mendez, Blanca; Hertz, Emil Peter Thrane; Schwarz, Jeanette; Pena, Hanna Sofia; Nikodemus, Denise; Kveiborg, Marie; Kettenbach, Arminja N.; Nilsson, Jakob.

In: EMBO Journal, Vol. 39, e103695, 2020.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Kruse, T, Gnosa, SP, Nasa, I, Garvanska, DH, Hein, JB, Nguyen, H, Samsøe-Petersen, J, Lopez-Mendez, B, Hertz, EPT, Schwarz, J, Pena, HS, Nikodemus, D, Kveiborg, M, Kettenbach, AN & Nilsson, J 2020, 'Mechanisms of site-specific dephosphorylation and kinase opposition imposed by PP2A regulatory subunits', EMBO Journal, vol. 39, e103695. https://doi.org/10.15252/embj.2019103695

APA

Kruse, T., Gnosa, S. P., Nasa, I., Garvanska, D. H., Hein, J. B., Nguyen, H., Samsøe-Petersen, J., Lopez-Mendez, B., Hertz, E. P. T., Schwarz, J., Pena, H. S., Nikodemus, D., Kveiborg, M., Kettenbach, A. N., & Nilsson, J. (2020). Mechanisms of site-specific dephosphorylation and kinase opposition imposed by PP2A regulatory subunits. EMBO Journal, 39, [e103695]. https://doi.org/10.15252/embj.2019103695

Vancouver

Kruse T, Gnosa SP, Nasa I, Garvanska DH, Hein JB, Nguyen H et al. Mechanisms of site-specific dephosphorylation and kinase opposition imposed by PP2A regulatory subunits. EMBO Journal. 2020;39. e103695. https://doi.org/10.15252/embj.2019103695

Author

Kruse, Thomas ; Gnosa, Sebastian Peter ; Nasa, Isha ; Garvanska, Dimitriya Hristoforova ; Hein, Jamin B. ; Nguyen, Hieu ; Samsøe-Petersen, Jacob ; Lopez-Mendez, Blanca ; Hertz, Emil Peter Thrane ; Schwarz, Jeanette ; Pena, Hanna Sofia ; Nikodemus, Denise ; Kveiborg, Marie ; Kettenbach, Arminja N. ; Nilsson, Jakob. / Mechanisms of site-specific dephosphorylation and kinase opposition imposed by PP2A regulatory subunits. In: EMBO Journal. 2020 ; Vol. 39.

Bibtex

@article{87bed1ea96e145a9a4598ecdeb119a47,
title = "Mechanisms of site-specific dephosphorylation and kinase opposition imposed by PP2A regulatory subunits",
abstract = "PP2A is an essential protein phosphatase that regulates most cellular processes through the formation of holoenzymes containing distinct regulatory B-subunits. Only a limited number of PP2A-regulated phosphorylation sites are known. This hampers our understanding of the mechanisms of site-specific dephosphorylation and of its tumor suppressor functions. Here, we develop phosphoproteomic strategies for global substrate identification of PP2A-B56 and PP2A-B55 holoenzymes. Strikingly, we find that B-subunits directly affect the dephosphorylation site preference of the PP2A catalytic subunit, resulting in unique patterns of kinase opposition. For PP2A-B56, these patterns are further modulated by affinity and position of B56 binding motifs. Our screens identify phosphorylation sites in the cancer target ADAM17 that are regulated through a conserved B56 binding site. Binding of PP2A-B56 to ADAM17 protease decreases growth factor signaling and tumor development in mice. This work provides a roadmap for the identification of phosphatase substrates and reveals unexpected mechanisms governing PP2A dephosphorylation site specificity and tumor suppressor function.",
keywords = "ADAM17, phosphoproteomics, PP2A, substrate specificity, tumor suppressor",
author = "Thomas Kruse and Gnosa, {Sebastian Peter} and Isha Nasa and Garvanska, {Dimitriya Hristoforova} and Hein, {Jamin B.} and Hieu Nguyen and Jacob Sams{\o}e-Petersen and Blanca Lopez-Mendez and Hertz, {Emil Peter Thrane} and Jeanette Schwarz and Pena, {Hanna Sofia} and Denise Nikodemus and Marie Kveiborg and Kettenbach, {Arminja N.} and Jakob Nilsson",
year = "2020",
doi = "10.15252/embj.2019103695",
language = "English",
volume = "39",
journal = "E M B O Journal",
issn = "0261-4189",
publisher = "Wiley-Blackwell",

}

RIS

TY - JOUR

T1 - Mechanisms of site-specific dephosphorylation and kinase opposition imposed by PP2A regulatory subunits

AU - Kruse, Thomas

AU - Gnosa, Sebastian Peter

AU - Nasa, Isha

AU - Garvanska, Dimitriya Hristoforova

AU - Hein, Jamin B.

AU - Nguyen, Hieu

AU - Samsøe-Petersen, Jacob

AU - Lopez-Mendez, Blanca

AU - Hertz, Emil Peter Thrane

AU - Schwarz, Jeanette

AU - Pena, Hanna Sofia

AU - Nikodemus, Denise

AU - Kveiborg, Marie

AU - Kettenbach, Arminja N.

AU - Nilsson, Jakob

PY - 2020

Y1 - 2020

N2 - PP2A is an essential protein phosphatase that regulates most cellular processes through the formation of holoenzymes containing distinct regulatory B-subunits. Only a limited number of PP2A-regulated phosphorylation sites are known. This hampers our understanding of the mechanisms of site-specific dephosphorylation and of its tumor suppressor functions. Here, we develop phosphoproteomic strategies for global substrate identification of PP2A-B56 and PP2A-B55 holoenzymes. Strikingly, we find that B-subunits directly affect the dephosphorylation site preference of the PP2A catalytic subunit, resulting in unique patterns of kinase opposition. For PP2A-B56, these patterns are further modulated by affinity and position of B56 binding motifs. Our screens identify phosphorylation sites in the cancer target ADAM17 that are regulated through a conserved B56 binding site. Binding of PP2A-B56 to ADAM17 protease decreases growth factor signaling and tumor development in mice. This work provides a roadmap for the identification of phosphatase substrates and reveals unexpected mechanisms governing PP2A dephosphorylation site specificity and tumor suppressor function.

AB - PP2A is an essential protein phosphatase that regulates most cellular processes through the formation of holoenzymes containing distinct regulatory B-subunits. Only a limited number of PP2A-regulated phosphorylation sites are known. This hampers our understanding of the mechanisms of site-specific dephosphorylation and of its tumor suppressor functions. Here, we develop phosphoproteomic strategies for global substrate identification of PP2A-B56 and PP2A-B55 holoenzymes. Strikingly, we find that B-subunits directly affect the dephosphorylation site preference of the PP2A catalytic subunit, resulting in unique patterns of kinase opposition. For PP2A-B56, these patterns are further modulated by affinity and position of B56 binding motifs. Our screens identify phosphorylation sites in the cancer target ADAM17 that are regulated through a conserved B56 binding site. Binding of PP2A-B56 to ADAM17 protease decreases growth factor signaling and tumor development in mice. This work provides a roadmap for the identification of phosphatase substrates and reveals unexpected mechanisms governing PP2A dephosphorylation site specificity and tumor suppressor function.

KW - ADAM17

KW - phosphoproteomics

KW - PP2A

KW - substrate specificity

KW - tumor suppressor

U2 - 10.15252/embj.2019103695

DO - 10.15252/embj.2019103695

M3 - Journal article

C2 - 32400009

AN - SCOPUS:85084413673

VL - 39

JO - E M B O Journal

JF - E M B O Journal

SN - 0261-4189

M1 - e103695

ER -

ID: 241750585