Differential roles of PI3-kinase and Kit tyrosine 821 in Kit receptor-mediated proliferation, survival and cell adhesion in mast cells

H. Serve, Nelson Shu-Sang Yee, G. Stella, L. Sepp-Lorenzino, J. C. Tan, P. Besmer

Research output: Contribution to journalArticle

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Abstract

The pleiotropic effects of the Kit receptor system are mediated by Kit-Ligand (KL) induced receptor autophosphorylation and its association with and activation of distinct second messengers, including phosphatidylinositol 3'-kinase (PI3-kinase), p21(ras) and mitogen-activated protein kinase (MAPK). To define the role of PI3-kinase, p21(ras) and MAPK in Kit-mediated cell proliferation, survival and adhesion in bone marrow-derived mast cells (BMMC), mutant Kit receptors were expressed in W(sh)/W(sh) BMMC lacking endogenous c-kit expression. The introduction of both murine Kit(S) and Kit(L) (isoform containing a four amino acid insert) into W(sh)/W(sh) BMMC restored KL-induced proliferation, survival and adhesion to fibronectin, as well as activation of PI3-kinase, p21(ras) and MAPK, and induced expression of c-fos, junB, c-myc and c-myb mRNA. Substitution of tyrosine 719 in the kinase insert with phenylalanine (Y719F) abolished PI3-kinase activation, diminished c-fos and junB induction, and impaired KL-induced adhesion of BMMC to fibronectin. In addition, the Y719F mutation had partial effects on p21(ras) activation, cell proliferation and survival, while MAP kinase activation was not affected. On the other hand, Y821F substitution impaired proliferation and survival without affecting PI3-kinase, p21(ras) and MAPK activation, and induction of c-myc, c-myb, c-fos and c-jun mRNA, while KL-induced cell adhesion to fibronectin remained intact. In agreement with a role for PI3-kinase in Kit-mediated cell adhesion, wortmannin blocked Kit-mediated cell adhesion at concentrations known to specifically inhibit PI3-kinase. We conclude, that association of Kit with p85(PI3-K), and thus with PI3-kinase activity, is necessary for a full mitogenic as well as adhesive response in mast cells. In contrast, tyrosine 821 is essential for Kit-mediated mitogenesis and survival, but not cell adhesion.

Original languageEnglish (US)
Pages (from-to)473-483
Number of pages11
JournalEMBO Journal
Volume14
Issue number3
StatePublished - 1995

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Phosphatidylinositol 3-Kinase
Cell adhesion
Mast Cells
Cell Adhesion
Tyrosine
Proto-Oncogene Proteins p21(ras)
Stem Cell Factor
Chemical activation
Mitogen-Activated Protein Kinases
Bone
Bone Marrow
Fibronectins
Cell proliferation
Cell Survival
Substitution reactions
Phosphotransferases
Adhesion
Cell Proliferation
Association reactions
Messenger RNA

All Science Journal Classification (ASJC) codes

  • Cell Biology
  • Genetics

Cite this

Serve, H. ; Yee, Nelson Shu-Sang ; Stella, G. ; Sepp-Lorenzino, L. ; Tan, J. C. ; Besmer, P. / Differential roles of PI3-kinase and Kit tyrosine 821 in Kit receptor-mediated proliferation, survival and cell adhesion in mast cells. In: EMBO Journal. 1995 ; Vol. 14, No. 3. pp. 473-483.
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abstract = "The pleiotropic effects of the Kit receptor system are mediated by Kit-Ligand (KL) induced receptor autophosphorylation and its association with and activation of distinct second messengers, including phosphatidylinositol 3'-kinase (PI3-kinase), p21(ras) and mitogen-activated protein kinase (MAPK). To define the role of PI3-kinase, p21(ras) and MAPK in Kit-mediated cell proliferation, survival and adhesion in bone marrow-derived mast cells (BMMC), mutant Kit receptors were expressed in W(sh)/W(sh) BMMC lacking endogenous c-kit expression. The introduction of both murine Kit(S) and Kit(L) (isoform containing a four amino acid insert) into W(sh)/W(sh) BMMC restored KL-induced proliferation, survival and adhesion to fibronectin, as well as activation of PI3-kinase, p21(ras) and MAPK, and induced expression of c-fos, junB, c-myc and c-myb mRNA. Substitution of tyrosine 719 in the kinase insert with phenylalanine (Y719F) abolished PI3-kinase activation, diminished c-fos and junB induction, and impaired KL-induced adhesion of BMMC to fibronectin. In addition, the Y719F mutation had partial effects on p21(ras) activation, cell proliferation and survival, while MAP kinase activation was not affected. On the other hand, Y821F substitution impaired proliferation and survival without affecting PI3-kinase, p21(ras) and MAPK activation, and induction of c-myc, c-myb, c-fos and c-jun mRNA, while KL-induced cell adhesion to fibronectin remained intact. In agreement with a role for PI3-kinase in Kit-mediated cell adhesion, wortmannin blocked Kit-mediated cell adhesion at concentrations known to specifically inhibit PI3-kinase. We conclude, that association of Kit with p85(PI3-K), and thus with PI3-kinase activity, is necessary for a full mitogenic as well as adhesive response in mast cells. In contrast, tyrosine 821 is essential for Kit-mediated mitogenesis and survival, but not cell adhesion.",
author = "H. Serve and Yee, {Nelson Shu-Sang} and G. Stella and L. Sepp-Lorenzino and Tan, {J. C.} and P. Besmer",
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Differential roles of PI3-kinase and Kit tyrosine 821 in Kit receptor-mediated proliferation, survival and cell adhesion in mast cells. / Serve, H.; Yee, Nelson Shu-Sang; Stella, G.; Sepp-Lorenzino, L.; Tan, J. C.; Besmer, P.

In: EMBO Journal, Vol. 14, No. 3, 1995, p. 473-483.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Differential roles of PI3-kinase and Kit tyrosine 821 in Kit receptor-mediated proliferation, survival and cell adhesion in mast cells

AU - Serve, H.

AU - Yee, Nelson Shu-Sang

AU - Stella, G.

AU - Sepp-Lorenzino, L.

AU - Tan, J. C.

AU - Besmer, P.

PY - 1995

Y1 - 1995

N2 - The pleiotropic effects of the Kit receptor system are mediated by Kit-Ligand (KL) induced receptor autophosphorylation and its association with and activation of distinct second messengers, including phosphatidylinositol 3'-kinase (PI3-kinase), p21(ras) and mitogen-activated protein kinase (MAPK). To define the role of PI3-kinase, p21(ras) and MAPK in Kit-mediated cell proliferation, survival and adhesion in bone marrow-derived mast cells (BMMC), mutant Kit receptors were expressed in W(sh)/W(sh) BMMC lacking endogenous c-kit expression. The introduction of both murine Kit(S) and Kit(L) (isoform containing a four amino acid insert) into W(sh)/W(sh) BMMC restored KL-induced proliferation, survival and adhesion to fibronectin, as well as activation of PI3-kinase, p21(ras) and MAPK, and induced expression of c-fos, junB, c-myc and c-myb mRNA. Substitution of tyrosine 719 in the kinase insert with phenylalanine (Y719F) abolished PI3-kinase activation, diminished c-fos and junB induction, and impaired KL-induced adhesion of BMMC to fibronectin. In addition, the Y719F mutation had partial effects on p21(ras) activation, cell proliferation and survival, while MAP kinase activation was not affected. On the other hand, Y821F substitution impaired proliferation and survival without affecting PI3-kinase, p21(ras) and MAPK activation, and induction of c-myc, c-myb, c-fos and c-jun mRNA, while KL-induced cell adhesion to fibronectin remained intact. In agreement with a role for PI3-kinase in Kit-mediated cell adhesion, wortmannin blocked Kit-mediated cell adhesion at concentrations known to specifically inhibit PI3-kinase. We conclude, that association of Kit with p85(PI3-K), and thus with PI3-kinase activity, is necessary for a full mitogenic as well as adhesive response in mast cells. In contrast, tyrosine 821 is essential for Kit-mediated mitogenesis and survival, but not cell adhesion.

AB - The pleiotropic effects of the Kit receptor system are mediated by Kit-Ligand (KL) induced receptor autophosphorylation and its association with and activation of distinct second messengers, including phosphatidylinositol 3'-kinase (PI3-kinase), p21(ras) and mitogen-activated protein kinase (MAPK). To define the role of PI3-kinase, p21(ras) and MAPK in Kit-mediated cell proliferation, survival and adhesion in bone marrow-derived mast cells (BMMC), mutant Kit receptors were expressed in W(sh)/W(sh) BMMC lacking endogenous c-kit expression. The introduction of both murine Kit(S) and Kit(L) (isoform containing a four amino acid insert) into W(sh)/W(sh) BMMC restored KL-induced proliferation, survival and adhesion to fibronectin, as well as activation of PI3-kinase, p21(ras) and MAPK, and induced expression of c-fos, junB, c-myc and c-myb mRNA. Substitution of tyrosine 719 in the kinase insert with phenylalanine (Y719F) abolished PI3-kinase activation, diminished c-fos and junB induction, and impaired KL-induced adhesion of BMMC to fibronectin. In addition, the Y719F mutation had partial effects on p21(ras) activation, cell proliferation and survival, while MAP kinase activation was not affected. On the other hand, Y821F substitution impaired proliferation and survival without affecting PI3-kinase, p21(ras) and MAPK activation, and induction of c-myc, c-myb, c-fos and c-jun mRNA, while KL-induced cell adhesion to fibronectin remained intact. In agreement with a role for PI3-kinase in Kit-mediated cell adhesion, wortmannin blocked Kit-mediated cell adhesion at concentrations known to specifically inhibit PI3-kinase. We conclude, that association of Kit with p85(PI3-K), and thus with PI3-kinase activity, is necessary for a full mitogenic as well as adhesive response in mast cells. In contrast, tyrosine 821 is essential for Kit-mediated mitogenesis and survival, but not cell adhesion.

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