A function for phosphatidylinositol 3-kinase β (p85α-p110β) in fibroblasts during mitogenesis

Requirement for insulin- and lysophosphatidic acid-mediated signal transduction

Serge Roche, J. Downward, Patrick Raynal, Sara Courtneidge

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121 Citations (Scopus)

Abstract

We have previously shown that phosphatidylinositol 3-kinase α (PI 3- Kα) (p85α-p110α) is required for DNA synthesis induced by various growth factors (S. Roche, M. Koegl, and S. A. Courtneidge, Proc. Natl. Acad. Sci. USA 91:9185-9189, 1994) in fibroblasts. In the present study, we have investigated the function of PI 3-Kβ (p85α-p110β) during mitogenesis. By using antibodies specific to p110β we showed that PI 3-Kβ is expressed in NIH 3T3 cells. PI 3-Kβ and PI 3-Kα have common features: PI 3-Kβ is tightly associated with a protein serine kinase that phosphorylates p85α, it interacts with the Src-middle T antigen complex and the activated platelet- derived growth factor (PDGF) receptor in fibroblasts in vivo, and it becomes tyrosine phosphorylated after PDGF stimulation. PI 3-Kβ was also activated in Swiss 3T3 and Cos7 cells stimulated with lysophosphatidic acid (LPA), a mitogen that interacts with a heterotrimeric G protein-coupled receptor. In contrast PI 3-Kα was activated to a lesser extent in these cells. Microinjection of neutralizing antibodies specific for p110β into quiescent fibroblasts inhibited DNA synthesis induced by both insulin and LPA but poorly affected PDGF receptor signaling. Therefore, PI 3-Kβ plays an important role in transmitting the mitogenic response induced by some, but not all, growth factors. Finally, we show that while oncogenic V12Ras interacts with type I PI 3-Ks, it could induce DNA synthesis in the absence of active PI 3-Kα and PI 3-Kβ, suggesting that Ras uses other effectors for DNA synthesis.

Original languageEnglish (US)
Pages (from-to)7119-7129
Number of pages11
JournalMolecular and Cellular Biology
Volume18
Issue number12
StatePublished - Dec 1998
Externally publishedYes

Fingerprint

Phosphatidylinositol 3-Kinase
Signal Transduction
Fibroblasts
Insulin
Platelet-Derived Growth Factor Receptors
DNA
Intercellular Signaling Peptides and Proteins
Swiss 3T3 Cells
Heterotrimeric GTP-Binding Proteins
NIH 3T3 Cells
Protein-Serine-Threonine Kinases
Viral Tumor Antigens
Platelet-Derived Growth Factor
Microinjections
G-Protein-Coupled Receptors
Neutralizing Antibodies
Mitogens
Tyrosine
lysophosphatidic acid
Antibodies

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

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title = "A function for phosphatidylinositol 3-kinase β (p85α-p110β) in fibroblasts during mitogenesis: Requirement for insulin- and lysophosphatidic acid-mediated signal transduction",
abstract = "We have previously shown that phosphatidylinositol 3-kinase α (PI 3- Kα) (p85α-p110α) is required for DNA synthesis induced by various growth factors (S. Roche, M. Koegl, and S. A. Courtneidge, Proc. Natl. Acad. Sci. USA 91:9185-9189, 1994) in fibroblasts. In the present study, we have investigated the function of PI 3-Kβ (p85α-p110β) during mitogenesis. By using antibodies specific to p110β we showed that PI 3-Kβ is expressed in NIH 3T3 cells. PI 3-Kβ and PI 3-Kα have common features: PI 3-Kβ is tightly associated with a protein serine kinase that phosphorylates p85α, it interacts with the Src-middle T antigen complex and the activated platelet- derived growth factor (PDGF) receptor in fibroblasts in vivo, and it becomes tyrosine phosphorylated after PDGF stimulation. PI 3-Kβ was also activated in Swiss 3T3 and Cos7 cells stimulated with lysophosphatidic acid (LPA), a mitogen that interacts with a heterotrimeric G protein-coupled receptor. In contrast PI 3-Kα was activated to a lesser extent in these cells. Microinjection of neutralizing antibodies specific for p110β into quiescent fibroblasts inhibited DNA synthesis induced by both insulin and LPA but poorly affected PDGF receptor signaling. Therefore, PI 3-Kβ plays an important role in transmitting the mitogenic response induced by some, but not all, growth factors. Finally, we show that while oncogenic V12Ras interacts with type I PI 3-Ks, it could induce DNA synthesis in the absence of active PI 3-Kα and PI 3-Kβ, suggesting that Ras uses other effectors for DNA synthesis.",
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