Expression of the high molecular weight fibroblast growth factor-2 isoform of 219 amino acids is associated with modulation of protein kinases C δ and ε and ERK activation

François Gaubert, Fabrice Escaffit, Claudine Bertrand, Murray Korc, Lucien Pradayrol, François Clemente, Agnés Estival

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

The high molecular weight (HMW) fibroblast growth factor (FGF)-2 isoform of 210 amino acids initiated at a CUG start codon possesses a nuclear localization sequence and is not secreted. In contrast, the low molecular weight (LMW) isoform of 155 amino acids initiated at the AUG start codon can be secreted and activates the cell surface FGF receptors. The two isoforms possess different biological properties; however, little is known about the intracrine regulatory mechanisms involved in the biological effects of the HMW FGF-2 isoform. Using pancreatic cells stably transfected with cDNAs leading to the expression of either the HMW FGF-2 (A3 cells) or the LMW form (A5 cells), we provide evidence that the two FGF-2 isoforms differentially modulate PKC levels. The LMW FGF-2 up-regulated the PKC ε levels by 1.6-fold; by contrast the HMW isoform down-regulated the level of this PKC isotype by about 3-fold and increased the amount of PKC δ by 1.7-fold. PKC mRNAs were also modified, suggesting that PKC expression was regulated at a pretransiational level. Additionally, expression of different levels of the HMW FGF-2 with an inducible expression system confirmed the role of this isoform on PKC δ and ε expressions. Increased activation of ERK-1 and -2 was also observed in cells expressing the HMW FGF-2. By using different PKC inhibitors and a dominant negative PKC δ, it was found that ERK activation was PKC δ-dependent. These data indicate that expression of HMW FGF-2 can modify PKC levels by acting at the intracellular level and that the overexpression of PKC δ induces ERK-1/2 activation. The expression of a dominant negative FGFR1 did not reduce ERK-1/2 activation by the HMW FGF-2, suggesting that ERK activation does not require FGFR activity. The signaling cascade downstream of ERK might be involved in the known mitogenic effect exerted by this FGF-2 isoform.

Original languageEnglish (US)
Pages (from-to)1545-1554
Number of pages10
JournalJournal of Biological Chemistry
Volume276
Issue number2
DOIs
StatePublished - Jan 12 2001
Externally publishedYes

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Fibroblast Growth Factor 2
Protein Kinase C
Protein Isoforms
Molecular Weight
Chemical activation
Molecular weight
Modulation
Amino Acids
Initiator Codon
Fibroblast Growth Factor Receptors
Complementary DNA
Cells
Messenger RNA

ASJC Scopus subject areas

  • Biochemistry

Cite this

Expression of the high molecular weight fibroblast growth factor-2 isoform of 219 amino acids is associated with modulation of protein kinases C δ and ε and ERK activation. / Gaubert, François; Escaffit, Fabrice; Bertrand, Claudine; Korc, Murray; Pradayrol, Lucien; Clemente, François; Estival, Agnés.

In: Journal of Biological Chemistry, Vol. 276, No. 2, 12.01.2001, p. 1545-1554.

Research output: Contribution to journalArticle

Gaubert, François ; Escaffit, Fabrice ; Bertrand, Claudine ; Korc, Murray ; Pradayrol, Lucien ; Clemente, François ; Estival, Agnés. / Expression of the high molecular weight fibroblast growth factor-2 isoform of 219 amino acids is associated with modulation of protein kinases C δ and ε and ERK activation. In: Journal of Biological Chemistry. 2001 ; Vol. 276, No. 2. pp. 1545-1554.
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abstract = "The high molecular weight (HMW) fibroblast growth factor (FGF)-2 isoform of 210 amino acids initiated at a CUG start codon possesses a nuclear localization sequence and is not secreted. In contrast, the low molecular weight (LMW) isoform of 155 amino acids initiated at the AUG start codon can be secreted and activates the cell surface FGF receptors. The two isoforms possess different biological properties; however, little is known about the intracrine regulatory mechanisms involved in the biological effects of the HMW FGF-2 isoform. Using pancreatic cells stably transfected with cDNAs leading to the expression of either the HMW FGF-2 (A3 cells) or the LMW form (A5 cells), we provide evidence that the two FGF-2 isoforms differentially modulate PKC levels. The LMW FGF-2 up-regulated the PKC ε levels by 1.6-fold; by contrast the HMW isoform down-regulated the level of this PKC isotype by about 3-fold and increased the amount of PKC δ by 1.7-fold. PKC mRNAs were also modified, suggesting that PKC expression was regulated at a pretransiational level. Additionally, expression of different levels of the HMW FGF-2 with an inducible expression system confirmed the role of this isoform on PKC δ and ε expressions. Increased activation of ERK-1 and -2 was also observed in cells expressing the HMW FGF-2. By using different PKC inhibitors and a dominant negative PKC δ, it was found that ERK activation was PKC δ-dependent. These data indicate that expression of HMW FGF-2 can modify PKC levels by acting at the intracellular level and that the overexpression of PKC δ induces ERK-1/2 activation. The expression of a dominant negative FGFR1 did not reduce ERK-1/2 activation by the HMW FGF-2, suggesting that ERK activation does not require FGFR activity. The signaling cascade downstream of ERK might be involved in the known mitogenic effect exerted by this FGF-2 isoform.",
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T1 - Expression of the high molecular weight fibroblast growth factor-2 isoform of 219 amino acids is associated with modulation of protein kinases C δ and ε and ERK activation

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AU - Estival, Agnés

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