Molecular mechanism of T-cell protein tyrosine phosphatase (TCPTP) activation by mitoxantrone

Mikko Ylilauri, Elina Mattila, Elisa M. Nurminen, Jarmo Käpylä, Sanna P. Niinivehmas, Juha A. Määttä, Ulla Pentikäinen, Johanna Ivaska, Olli T. Pentikäinen (Corresponding Author)

Research output: Contribution to journalArticleScientificpeer-review

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Abstract

T-cell protein tyrosine phosphatase (TCPTP) is a ubiquitously expressed non-receptor protein tyrosine phosphatase. It is involved in the negative regulation of many cellular signaling pathways. Thus, activation of TCPTP could have important therapeutic applications in diseases such as cancer and inflammation. We have previously shown that the α-cytoplasmic tail of integrin α1β1 directly binds and activates TCPTP. In addition, we have identified in a large-scale high-throughput screen six small molecules that activate TCPTP. These small molecule activators include mitoxantrone and spermidine. In this study, we have investigated the molecular mechanism behind agonist-induced TCPTP activation. By combining several molecular modeling and biochemical techniques, we demonstrate that α1-peptide and mitoxantrone activate TCPTP via direct binding to the catalytic domain, whereas spermidine does not interact with the catalytic domain of TCPTP in vitro. Furthermore, we have identified a hydrophobic groove surrounded by negatively charged residues on the surface of TCPTP as a putative binding site for the α1-peptide and mitoxantrone. Importantly, these data have allowed us to identify a new molecule that binds to TCPTP, but interestingly cannot activate its phosphatase activity. Accordingly, we describe here mechanism of TCPTP activation by mitoxantrone, the cytoplasmic tail of α1-integrin, and a mitoxantrone-like molecule at the atomic level. These data provide invaluable insight into the development of novel TCPTP activators, and may facilitate the rational discovery of small-molecule cancer therapeutics.
Original languageEnglish
Pages (from-to)1988-1997
JournalBiochimica et Biophysica Acta: Proteins and Proteomics
Volume1834
Issue number10
DOIs
Publication statusPublished - 2013
MoE publication typeA1 Journal article-refereed

Fingerprint

Non-Receptor Type 2 Protein Tyrosine Phosphatase
Mitoxantrone
Chemical activation
Molecules
Spermidine
Integrins
Non-Receptor Protein Tyrosine Phosphatases
Catalytic Domain
Cell signaling
Peptides
Molecular modeling
Phosphoric Monoester Hydrolases

Keywords

  • differential scanning fluorimetry
  • integrin
  • isothermal titration calorimetry
  • mitoxantrone
  • molecular dynamics simulation
  • T-cell protein tyrosine phosphatase

Cite this

Ylilauri, M., Mattila, E., Nurminen, E. M., Käpylä, J., Niinivehmas, S. P., Määttä, J. A., ... Pentikäinen, O. T. (2013). Molecular mechanism of T-cell protein tyrosine phosphatase (TCPTP) activation by mitoxantrone. Biochimica et Biophysica Acta: Proteins and Proteomics, 1834(10), 1988-1997. https://doi.org/10.1016/j.bbapap.2013.07.001
Ylilauri, Mikko ; Mattila, Elina ; Nurminen, Elisa M. ; Käpylä, Jarmo ; Niinivehmas, Sanna P. ; Määttä, Juha A. ; Pentikäinen, Ulla ; Ivaska, Johanna ; Pentikäinen, Olli T. / Molecular mechanism of T-cell protein tyrosine phosphatase (TCPTP) activation by mitoxantrone. In: Biochimica et Biophysica Acta: Proteins and Proteomics. 2013 ; Vol. 1834, No. 10. pp. 1988-1997.
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abstract = "T-cell protein tyrosine phosphatase (TCPTP) is a ubiquitously expressed non-receptor protein tyrosine phosphatase. It is involved in the negative regulation of many cellular signaling pathways. Thus, activation of TCPTP could have important therapeutic applications in diseases such as cancer and inflammation. We have previously shown that the α-cytoplasmic tail of integrin α1β1 directly binds and activates TCPTP. In addition, we have identified in a large-scale high-throughput screen six small molecules that activate TCPTP. These small molecule activators include mitoxantrone and spermidine. In this study, we have investigated the molecular mechanism behind agonist-induced TCPTP activation. By combining several molecular modeling and biochemical techniques, we demonstrate that α1-peptide and mitoxantrone activate TCPTP via direct binding to the catalytic domain, whereas spermidine does not interact with the catalytic domain of TCPTP in vitro. Furthermore, we have identified a hydrophobic groove surrounded by negatively charged residues on the surface of TCPTP as a putative binding site for the α1-peptide and mitoxantrone. Importantly, these data have allowed us to identify a new molecule that binds to TCPTP, but interestingly cannot activate its phosphatase activity. Accordingly, we describe here mechanism of TCPTP activation by mitoxantrone, the cytoplasmic tail of α1-integrin, and a mitoxantrone-like molecule at the atomic level. These data provide invaluable insight into the development of novel TCPTP activators, and may facilitate the rational discovery of small-molecule cancer therapeutics.",
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Ylilauri, M, Mattila, E, Nurminen, EM, Käpylä, J, Niinivehmas, SP, Määttä, JA, Pentikäinen, U, Ivaska, J & Pentikäinen, OT 2013, 'Molecular mechanism of T-cell protein tyrosine phosphatase (TCPTP) activation by mitoxantrone', Biochimica et Biophysica Acta: Proteins and Proteomics, vol. 1834, no. 10, pp. 1988-1997. https://doi.org/10.1016/j.bbapap.2013.07.001

Molecular mechanism of T-cell protein tyrosine phosphatase (TCPTP) activation by mitoxantrone. / Ylilauri, Mikko; Mattila, Elina; Nurminen, Elisa M.; Käpylä, Jarmo; Niinivehmas, Sanna P.; Määttä, Juha A.; Pentikäinen, Ulla; Ivaska, Johanna; Pentikäinen, Olli T. (Corresponding Author).

In: Biochimica et Biophysica Acta: Proteins and Proteomics, Vol. 1834, No. 10, 2013, p. 1988-1997.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Molecular mechanism of T-cell protein tyrosine phosphatase (TCPTP) activation by mitoxantrone

AU - Ylilauri, Mikko

AU - Mattila, Elina

AU - Nurminen, Elisa M.

AU - Käpylä, Jarmo

AU - Niinivehmas, Sanna P.

AU - Määttä, Juha A.

AU - Pentikäinen, Ulla

AU - Ivaska, Johanna

AU - Pentikäinen, Olli T.

PY - 2013

Y1 - 2013

N2 - T-cell protein tyrosine phosphatase (TCPTP) is a ubiquitously expressed non-receptor protein tyrosine phosphatase. It is involved in the negative regulation of many cellular signaling pathways. Thus, activation of TCPTP could have important therapeutic applications in diseases such as cancer and inflammation. We have previously shown that the α-cytoplasmic tail of integrin α1β1 directly binds and activates TCPTP. In addition, we have identified in a large-scale high-throughput screen six small molecules that activate TCPTP. These small molecule activators include mitoxantrone and spermidine. In this study, we have investigated the molecular mechanism behind agonist-induced TCPTP activation. By combining several molecular modeling and biochemical techniques, we demonstrate that α1-peptide and mitoxantrone activate TCPTP via direct binding to the catalytic domain, whereas spermidine does not interact with the catalytic domain of TCPTP in vitro. Furthermore, we have identified a hydrophobic groove surrounded by negatively charged residues on the surface of TCPTP as a putative binding site for the α1-peptide and mitoxantrone. Importantly, these data have allowed us to identify a new molecule that binds to TCPTP, but interestingly cannot activate its phosphatase activity. Accordingly, we describe here mechanism of TCPTP activation by mitoxantrone, the cytoplasmic tail of α1-integrin, and a mitoxantrone-like molecule at the atomic level. These data provide invaluable insight into the development of novel TCPTP activators, and may facilitate the rational discovery of small-molecule cancer therapeutics.

AB - T-cell protein tyrosine phosphatase (TCPTP) is a ubiquitously expressed non-receptor protein tyrosine phosphatase. It is involved in the negative regulation of many cellular signaling pathways. Thus, activation of TCPTP could have important therapeutic applications in diseases such as cancer and inflammation. We have previously shown that the α-cytoplasmic tail of integrin α1β1 directly binds and activates TCPTP. In addition, we have identified in a large-scale high-throughput screen six small molecules that activate TCPTP. These small molecule activators include mitoxantrone and spermidine. In this study, we have investigated the molecular mechanism behind agonist-induced TCPTP activation. By combining several molecular modeling and biochemical techniques, we demonstrate that α1-peptide and mitoxantrone activate TCPTP via direct binding to the catalytic domain, whereas spermidine does not interact with the catalytic domain of TCPTP in vitro. Furthermore, we have identified a hydrophobic groove surrounded by negatively charged residues on the surface of TCPTP as a putative binding site for the α1-peptide and mitoxantrone. Importantly, these data have allowed us to identify a new molecule that binds to TCPTP, but interestingly cannot activate its phosphatase activity. Accordingly, we describe here mechanism of TCPTP activation by mitoxantrone, the cytoplasmic tail of α1-integrin, and a mitoxantrone-like molecule at the atomic level. These data provide invaluable insight into the development of novel TCPTP activators, and may facilitate the rational discovery of small-molecule cancer therapeutics.

KW - differential scanning fluorimetry

KW - integrin

KW - isothermal titration calorimetry

KW - mitoxantrone

KW - molecular dynamics simulation

KW - T-cell protein tyrosine phosphatase

U2 - 10.1016/j.bbapap.2013.07.001

DO - 10.1016/j.bbapap.2013.07.001

M3 - Article

VL - 1834

SP - 1988

EP - 1997

JO - Biochimica et Biophysica Acta: Proteins and Proteomics

JF - Biochimica et Biophysica Acta: Proteins and Proteomics

SN - 1570-9639

IS - 10

ER -