The inositol 5-phosphatase SHIP1 is a nucleo-cytoplasmic shuttling protein and enzymatically active in cell nuclei.
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The inositol 5-phosphatase SHIP1 is a nucleo-cytoplasmic shuttling protein and enzymatically active in cell nuclei. / Nalaskowski, Marcus; Metzner, Anja; Brehm, Maria; Labiadh, Sena; Brauer, Helena; Grabinski, Nicole; Mayr, Georg W.; Jücker, Manfred.
In: CELL SIGNAL, Vol. 24, No. 3, 3, 2012, p. 621-628.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - The inositol 5-phosphatase SHIP1 is a nucleo-cytoplasmic shuttling protein and enzymatically active in cell nuclei.
AU - Nalaskowski, Marcus
AU - Metzner, Anja
AU - Brehm, Maria
AU - Labiadh, Sena
AU - Brauer, Helena
AU - Grabinski, Nicole
AU - Mayr, Georg W.
AU - Jücker, Manfred
PY - 2012
Y1 - 2012
N2 - The inositol 5-phosphatase SHIP1 is a negative regulator of signaling processes in hematopoietic cells. SHIP1 mediates its regulatory function after relocalization from the cytoplasm to the plasma membrane where it converts its substrate PI(3,4,5)P(3) to PI(3,4)P(2) thereby terminating PI3-kinase mediated signaling. In addition, SHIP1 converts Ins(1,3,4,5)P(4) to Ins(1,3,4)P(3) thereby regulating inositol phosphate metabolism. Here we report, that SHIP1 can be detected in nuclear puncta of Jurkat cells by confocal microscopy after expression of SHIP1 from a tetracycline inducible vector. SHIP1-containing nuclear puncta partially co-localize with FLASH, a multifunctional nuclear protein that has been linked to apoptotic signaling and transcriptional control. Nuclear localization was confirmed for endogenously expressed SHIP1 in the myeloid leukemia cell line TF1. In addition, enzymatically active SHIP1 was found in nuclear fractions of Jurkat cells with a similar specific activity as cytoplasmic SHIP1. Further analysis revealed that SHIP1 is a nucleocytoplasmic shuttling protein which is actively imported into and exported out of the nucleus. Nuclear import is mediated by two canonical nuclear localization signals (NLS) i.e. K(327)KSK and K(547)KLR. Mutational inactivation of each NLS motif inhibited nuclear import and reduced the proliferation of cells indicating a functional role of nuclear SHIP1 for cell growth. Our data indicate that SHIP1 is partly localized in the nucleus and suggest that SHIP1 plays a role for nuclear phosphoinositide and/or nuclear inositol phosphate signaling.
AB - The inositol 5-phosphatase SHIP1 is a negative regulator of signaling processes in hematopoietic cells. SHIP1 mediates its regulatory function after relocalization from the cytoplasm to the plasma membrane where it converts its substrate PI(3,4,5)P(3) to PI(3,4)P(2) thereby terminating PI3-kinase mediated signaling. In addition, SHIP1 converts Ins(1,3,4,5)P(4) to Ins(1,3,4)P(3) thereby regulating inositol phosphate metabolism. Here we report, that SHIP1 can be detected in nuclear puncta of Jurkat cells by confocal microscopy after expression of SHIP1 from a tetracycline inducible vector. SHIP1-containing nuclear puncta partially co-localize with FLASH, a multifunctional nuclear protein that has been linked to apoptotic signaling and transcriptional control. Nuclear localization was confirmed for endogenously expressed SHIP1 in the myeloid leukemia cell line TF1. In addition, enzymatically active SHIP1 was found in nuclear fractions of Jurkat cells with a similar specific activity as cytoplasmic SHIP1. Further analysis revealed that SHIP1 is a nucleocytoplasmic shuttling protein which is actively imported into and exported out of the nucleus. Nuclear import is mediated by two canonical nuclear localization signals (NLS) i.e. K(327)KSK and K(547)KLR. Mutational inactivation of each NLS motif inhibited nuclear import and reduced the proliferation of cells indicating a functional role of nuclear SHIP1 for cell growth. Our data indicate that SHIP1 is partly localized in the nucleus and suggest that SHIP1 plays a role for nuclear phosphoinositide and/or nuclear inositol phosphate signaling.
KW - Humans
KW - Cell Line, Tumor
KW - Amino Acid Motifs
KW - Signal Transduction
KW - Cell Proliferation
KW - Mutagenesis, Site-Directed
KW - Apoptosis Regulatory Proteins/metabolism
KW - Calcium-Binding Proteins/metabolism
KW - Cell Nucleus/enzymology
KW - Nuclear Localization Signals/metabolism
KW - Phosphoric Monoester Hydrolases/analysis/genetics/metabolism
KW - Recombinant Fusion Proteins/analysis/genetics/metabolism
KW - Humans
KW - Cell Line, Tumor
KW - Amino Acid Motifs
KW - Signal Transduction
KW - Cell Proliferation
KW - Mutagenesis, Site-Directed
KW - Apoptosis Regulatory Proteins/metabolism
KW - Calcium-Binding Proteins/metabolism
KW - Cell Nucleus/enzymology
KW - Nuclear Localization Signals/metabolism
KW - Phosphoric Monoester Hydrolases/analysis/genetics/metabolism
KW - Recombinant Fusion Proteins/analysis/genetics/metabolism
M3 - SCORING: Journal article
VL - 24
SP - 621
EP - 628
JO - CELL SIGNAL
JF - CELL SIGNAL
SN - 0898-6568
IS - 3
M1 - 3
ER -
