Regulation of the Src Homology 2-containing Inositol 5-Phosphatase SHIP1 in HIP1/PDGFβR-transformed Cells

Djenann Saint-Dic, Samantha C. Chang, Gregory S. Taylor, Melissa M. Provot, Theodora S. Ross

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

It has been shown previously that the Huntingtin interacting protein 1 gene (HIP1) was fused to the platelet-derived growth factor β receptor gene (PDGFβR) in leukemic cells of a patient with chronic myelomonocytic leukemia. This resulted in the expression of the chimeric HIP1/PDGFβR protein, which oligomerizes, is constitutively tyrosine-phosphorylated, and transforms the Ba/F3 murine hematopoietic cell line to interleukin-3-independent growth. Tyrosine phosphorylation of a 130-kDa protein (p130) correlates with transformation by HIP1/PDGFβR and related transforming mutants. We report here that the p130 band is immunologically related to the 125-kDa isoform of the Src homology 2-containing inositol 5-phosphatase, SHIP1. We have found that SHIP1 associates and colocalizes with the HIP1/PDGFβR fusion protein and related transforming mutants. These mutants include a mutant that has eight Src homology 2-binding phosphotyrosines mutated to phenylalanine. In contrast, SHIP1 does not associate with H/P(KI), the kinase-dead form of HIP1/PDGFβR. We also report that phosphorylation of SHIP1 by HIP1/PDGFβR does not change its 5-phosphatase-specific activity. This suggests that phosphorylation and possible PDGFβR-mediated sequestration of SHIP1 from its substrates (PtdIns(3,4,5)P3 and Ins(1,3,4,5)P4) might alter the levels of these inositol-containing signal transduction molecules, resulting in activation of downstream effectors of cellular proliferation and/or survival.

Original languageEnglish (US)
Pages (from-to)21192-21198
Number of pages7
JournalJournal of Biological Chemistry
Volume276
Issue number24
DOIs
StatePublished - Jun 15 2001

Fingerprint

Platelet-Derived Growth Factor Receptors
Inositol
Phosphoric Monoester Hydrolases
Genes
Proteins
Phosphorylation
Tyrosine
Huntingtin Protein
Inositol Polyphosphate 5-Phosphatases
Leukemia, Myelomonocytic, Chronic
Cells
Phosphotyrosine
Interleukin-3
Gene Fusion
Signal transduction
Phenylalanine
Oncogenes
Signal Transduction
Protein Isoforms
Phosphotransferases

ASJC Scopus subject areas

  • Biochemistry

Cite this

Regulation of the Src Homology 2-containing Inositol 5-Phosphatase SHIP1 in HIP1/PDGFβR-transformed Cells. / Saint-Dic, Djenann; Chang, Samantha C.; Taylor, Gregory S.; Provot, Melissa M.; Ross, Theodora S.

In: Journal of Biological Chemistry, Vol. 276, No. 24, 15.06.2001, p. 21192-21198.

Research output: Contribution to journalArticle

Saint-Dic, Djenann ; Chang, Samantha C. ; Taylor, Gregory S. ; Provot, Melissa M. ; Ross, Theodora S. / Regulation of the Src Homology 2-containing Inositol 5-Phosphatase SHIP1 in HIP1/PDGFβR-transformed Cells. In: Journal of Biological Chemistry. 2001 ; Vol. 276, No. 24. pp. 21192-21198.
@article{1a0d845fca924e31a03f841cad9ed55e,
title = "Regulation of the Src Homology 2-containing Inositol 5-Phosphatase SHIP1 in HIP1/PDGFβR-transformed Cells",
abstract = "It has been shown previously that the Huntingtin interacting protein 1 gene (HIP1) was fused to the platelet-derived growth factor β receptor gene (PDGFβR) in leukemic cells of a patient with chronic myelomonocytic leukemia. This resulted in the expression of the chimeric HIP1/PDGFβR protein, which oligomerizes, is constitutively tyrosine-phosphorylated, and transforms the Ba/F3 murine hematopoietic cell line to interleukin-3-independent growth. Tyrosine phosphorylation of a 130-kDa protein (p130) correlates with transformation by HIP1/PDGFβR and related transforming mutants. We report here that the p130 band is immunologically related to the 125-kDa isoform of the Src homology 2-containing inositol 5-phosphatase, SHIP1. We have found that SHIP1 associates and colocalizes with the HIP1/PDGFβR fusion protein and related transforming mutants. These mutants include a mutant that has eight Src homology 2-binding phosphotyrosines mutated to phenylalanine. In contrast, SHIP1 does not associate with H/P(KI), the kinase-dead form of HIP1/PDGFβR. We also report that phosphorylation of SHIP1 by HIP1/PDGFβR does not change its 5-phosphatase-specific activity. This suggests that phosphorylation and possible PDGFβR-mediated sequestration of SHIP1 from its substrates (PtdIns(3,4,5)P3 and Ins(1,3,4,5)P4) might alter the levels of these inositol-containing signal transduction molecules, resulting in activation of downstream effectors of cellular proliferation and/or survival.",
author = "Djenann Saint-Dic and Chang, {Samantha C.} and Taylor, {Gregory S.} and Provot, {Melissa M.} and Ross, {Theodora S.}",
year = "2001",
month = "6",
day = "15",
doi = "10.1074/jbc.M008336200",
language = "English (US)",
volume = "276",
pages = "21192--21198",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "24",

}

TY - JOUR

T1 - Regulation of the Src Homology 2-containing Inositol 5-Phosphatase SHIP1 in HIP1/PDGFβR-transformed Cells

AU - Saint-Dic, Djenann

AU - Chang, Samantha C.

AU - Taylor, Gregory S.

AU - Provot, Melissa M.

AU - Ross, Theodora S.

PY - 2001/6/15

Y1 - 2001/6/15

N2 - It has been shown previously that the Huntingtin interacting protein 1 gene (HIP1) was fused to the platelet-derived growth factor β receptor gene (PDGFβR) in leukemic cells of a patient with chronic myelomonocytic leukemia. This resulted in the expression of the chimeric HIP1/PDGFβR protein, which oligomerizes, is constitutively tyrosine-phosphorylated, and transforms the Ba/F3 murine hematopoietic cell line to interleukin-3-independent growth. Tyrosine phosphorylation of a 130-kDa protein (p130) correlates with transformation by HIP1/PDGFβR and related transforming mutants. We report here that the p130 band is immunologically related to the 125-kDa isoform of the Src homology 2-containing inositol 5-phosphatase, SHIP1. We have found that SHIP1 associates and colocalizes with the HIP1/PDGFβR fusion protein and related transforming mutants. These mutants include a mutant that has eight Src homology 2-binding phosphotyrosines mutated to phenylalanine. In contrast, SHIP1 does not associate with H/P(KI), the kinase-dead form of HIP1/PDGFβR. We also report that phosphorylation of SHIP1 by HIP1/PDGFβR does not change its 5-phosphatase-specific activity. This suggests that phosphorylation and possible PDGFβR-mediated sequestration of SHIP1 from its substrates (PtdIns(3,4,5)P3 and Ins(1,3,4,5)P4) might alter the levels of these inositol-containing signal transduction molecules, resulting in activation of downstream effectors of cellular proliferation and/or survival.

AB - It has been shown previously that the Huntingtin interacting protein 1 gene (HIP1) was fused to the platelet-derived growth factor β receptor gene (PDGFβR) in leukemic cells of a patient with chronic myelomonocytic leukemia. This resulted in the expression of the chimeric HIP1/PDGFβR protein, which oligomerizes, is constitutively tyrosine-phosphorylated, and transforms the Ba/F3 murine hematopoietic cell line to interleukin-3-independent growth. Tyrosine phosphorylation of a 130-kDa protein (p130) correlates with transformation by HIP1/PDGFβR and related transforming mutants. We report here that the p130 band is immunologically related to the 125-kDa isoform of the Src homology 2-containing inositol 5-phosphatase, SHIP1. We have found that SHIP1 associates and colocalizes with the HIP1/PDGFβR fusion protein and related transforming mutants. These mutants include a mutant that has eight Src homology 2-binding phosphotyrosines mutated to phenylalanine. In contrast, SHIP1 does not associate with H/P(KI), the kinase-dead form of HIP1/PDGFβR. We also report that phosphorylation of SHIP1 by HIP1/PDGFβR does not change its 5-phosphatase-specific activity. This suggests that phosphorylation and possible PDGFβR-mediated sequestration of SHIP1 from its substrates (PtdIns(3,4,5)P3 and Ins(1,3,4,5)P4) might alter the levels of these inositol-containing signal transduction molecules, resulting in activation of downstream effectors of cellular proliferation and/or survival.

UR - http://www.scopus.com/inward/record.url?scp=0035877597&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0035877597&partnerID=8YFLogxK

U2 - 10.1074/jbc.M008336200

DO - 10.1074/jbc.M008336200

M3 - Article

C2 - 11287412

AN - SCOPUS:0035877597

VL - 276

SP - 21192

EP - 21198

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 24

ER -