Differential regulation of MAP kinase activation by a novel splice variant of human MAP kinase phosphatase-2

C. Cadalbert, C.M. Sloss, M.M. Cunningham, M. Al-Muteiri, A. McIntire, J. Shipley, R. Plevin

Research output: Contribution to journal › Article

10 Citations (Scopus)

Abstract

MAP kinase phosphatase-2 (MKP-2) is a member of the family of dual specificity phosphatases that functions to inactivate the ERK and JNK MAP kinase signalling pathways. Here, we identify a novel human MKP-2 variant (MKP-2-S) lacking the MAP kinase binding site but retaining the phosphatase catalytic domain. Endogenous MKP-2-S transcripts and proteins were found in PC3 prostate and MDA-MB-231 breast cancer cells and also human prostate biopsies. Cellular transfection of MKP-2-S gave rise to a nuclear protein of 33 kDa which displayed phosphatase activity comparable to the formerly described long form of MKP-2 (MKP-2-L). Due to its lack of a kinase interacting motif (KIM), MKP-2-S did not bind to JNK or ERK; MKP-2-L bound ERK and to a lesser extent JNK. Protein turnover of adenoviral expressed MKP-2-S was accelerated relative to MKP-2-L, with a greater susceptibility to proteosomal-mediated degradation. MKP-2-S retained its ability to deactivate JNK in a similar manner as MKP-2-L and was an effective inhibitor of LPS-stimulated COX-2 induction. However, unlike MKP-2-L, MKP-2-S was unable to reverse serum-induced ERK activation or significantly inhibit endothelial cell proliferation. These findings reveal the occurrence of a novel splice variant of MKP-2 which is unable to bind ERK and may be significant in the dysregulation of MAP kinase activity in certain disease states, particularly in breast and prostate cancers.
LanguageEnglish
Pages357-365
Number of pages9
JournalCellular Signalling
Volume22
Issue number3
DOIs
Publication statusPublished - Mar 2009

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Mitogen-Activated Protein Kinase 1
Phosphoric Monoester Hydrolases
Phosphotransferases
Extracellular Signal-Regulated MAP Kinases
Prostate
Dual-Specificity Phosphatases
MAP Kinase Kinase 4
Breast Neoplasms
Aptitude
MAP Kinase Signaling System
Protein S
Nuclear Proteins

Keywords

  • map kinase phosphatase
  • map kinase
  • tyrosine kinase
  • pharmacology

Cite this

Cadalbert, C. ; Sloss, C.M. ; Cunningham, M.M. ; Al-Muteiri, M. ; McIntire, A. ; Shipley, J. ; Plevin, R. / Differential regulation of MAP kinase activation by a novel splice variant of human MAP kinase phosphatase-2. In: Cellular Signalling. 2009 ; Vol. 22, No. 3. pp. 357-365.
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abstract = "MAP kinase phosphatase-2 (MKP-2) is a member of the family of dual specificity phosphatases that functions to inactivate the ERK and JNK MAP kinase signalling pathways. Here, we identify a novel human MKP-2 variant (MKP-2-S) lacking the MAP kinase binding site but retaining the phosphatase catalytic domain. Endogenous MKP-2-S transcripts and proteins were found in PC3 prostate and MDA-MB-231 breast cancer cells and also human prostate biopsies. Cellular transfection of MKP-2-S gave rise to a nuclear protein of 33 kDa which displayed phosphatase activity comparable to the formerly described long form of MKP-2 (MKP-2-L). Due to its lack of a kinase interacting motif (KIM), MKP-2-S did not bind to JNK or ERK; MKP-2-L bound ERK and to a lesser extent JNK. Protein turnover of adenoviral expressed MKP-2-S was accelerated relative to MKP-2-L, with a greater susceptibility to proteosomal-mediated degradation. MKP-2-S retained its ability to deactivate JNK in a similar manner as MKP-2-L and was an effective inhibitor of LPS-stimulated COX-2 induction. However, unlike MKP-2-L, MKP-2-S was unable to reverse serum-induced ERK activation or significantly inhibit endothelial cell proliferation. These findings reveal the occurrence of a novel splice variant of MKP-2 which is unable to bind ERK and may be significant in the dysregulation of MAP kinase activity in certain disease states, particularly in breast and prostate cancers.",
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Cadalbert, C, Sloss, CM, Cunningham, MM, Al-Muteiri, M, McIntire, A, Shipley, J & Plevin, R 2009, 'Differential regulation of MAP kinase activation by a novel splice variant of human MAP kinase phosphatase-2' Cellular Signalling, vol. 22, no. 3, pp. 357-365. https://doi.org/10.1016/j.cellsig.2009.10.002

Differential regulation of MAP kinase activation by a novel splice variant of human MAP kinase phosphatase-2. / Cadalbert, C.; Sloss, C.M.; Cunningham, M.M.; Al-Muteiri, M.; McIntire, A.; Shipley, J.; Plevin, R.

In: Cellular Signalling, Vol. 22, No. 3, 03.2009, p. 357-365.

Research output: Contribution to journal › Article

TY - JOUR

T1 - Differential regulation of MAP kinase activation by a novel splice variant of human MAP kinase phosphatase-2

AU - Cadalbert, C.

AU - Sloss, C.M.

AU - Cunningham, M.M.

AU - Al-Muteiri, M.

AU - McIntire, A.

AU - Shipley, J.

AU - Plevin, R.

PY - 2009/3

Y1 - 2009/3

N2 - MAP kinase phosphatase-2 (MKP-2) is a member of the family of dual specificity phosphatases that functions to inactivate the ERK and JNK MAP kinase signalling pathways. Here, we identify a novel human MKP-2 variant (MKP-2-S) lacking the MAP kinase binding site but retaining the phosphatase catalytic domain. Endogenous MKP-2-S transcripts and proteins were found in PC3 prostate and MDA-MB-231 breast cancer cells and also human prostate biopsies. Cellular transfection of MKP-2-S gave rise to a nuclear protein of 33 kDa which displayed phosphatase activity comparable to the formerly described long form of MKP-2 (MKP-2-L). Due to its lack of a kinase interacting motif (KIM), MKP-2-S did not bind to JNK or ERK; MKP-2-L bound ERK and to a lesser extent JNK. Protein turnover of adenoviral expressed MKP-2-S was accelerated relative to MKP-2-L, with a greater susceptibility to proteosomal-mediated degradation. MKP-2-S retained its ability to deactivate JNK in a similar manner as MKP-2-L and was an effective inhibitor of LPS-stimulated COX-2 induction. However, unlike MKP-2-L, MKP-2-S was unable to reverse serum-induced ERK activation or significantly inhibit endothelial cell proliferation. These findings reveal the occurrence of a novel splice variant of MKP-2 which is unable to bind ERK and may be significant in the dysregulation of MAP kinase activity in certain disease states, particularly in breast and prostate cancers.

AB - MAP kinase phosphatase-2 (MKP-2) is a member of the family of dual specificity phosphatases that functions to inactivate the ERK and JNK MAP kinase signalling pathways. Here, we identify a novel human MKP-2 variant (MKP-2-S) lacking the MAP kinase binding site but retaining the phosphatase catalytic domain. Endogenous MKP-2-S transcripts and proteins were found in PC3 prostate and MDA-MB-231 breast cancer cells and also human prostate biopsies. Cellular transfection of MKP-2-S gave rise to a nuclear protein of 33 kDa which displayed phosphatase activity comparable to the formerly described long form of MKP-2 (MKP-2-L). Due to its lack of a kinase interacting motif (KIM), MKP-2-S did not bind to JNK or ERK; MKP-2-L bound ERK and to a lesser extent JNK. Protein turnover of adenoviral expressed MKP-2-S was accelerated relative to MKP-2-L, with a greater susceptibility to proteosomal-mediated degradation. MKP-2-S retained its ability to deactivate JNK in a similar manner as MKP-2-L and was an effective inhibitor of LPS-stimulated COX-2 induction. However, unlike MKP-2-L, MKP-2-S was unable to reverse serum-induced ERK activation or significantly inhibit endothelial cell proliferation. These findings reveal the occurrence of a novel splice variant of MKP-2 which is unable to bind ERK and may be significant in the dysregulation of MAP kinase activity in certain disease states, particularly in breast and prostate cancers.

KW - map kinase phosphatase

KW - map kinase

KW - tyrosine kinase

KW - pharmacology

U2 - 10.1016/j.cellsig.2009.10.002

DO - 10.1016/j.cellsig.2009.10.002

M3 - Article

VL - 22

SP - 357

EP - 365

JO - Cellular Signalling

T2 - Cellular Signalling

JF - Cellular Signalling

SN - 0898-6568

IS - 3

ER -

Cadalbert C, Sloss CM, Cunningham MM, Al-Muteiri M, McIntire A, Shipley J et al. Differential regulation of MAP kinase activation by a novel splice variant of human MAP kinase phosphatase-2. Cellular Signalling. 2009 Mar;22(3):357-365. https://doi.org/10.1016/j.cellsig.2009.10.002

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