Bisindolylmaleimide I suppresses fibroblast growth factor-mediated activation of Erk MAP kinase in chondrocytes by preventing Shp2 association with the Frs2 and Gab1 adaptor proteins.

KREJČÍ, Pavel, B. MASRI, L. SALAZAR, C. FARRINGTON-ROCK, H. PRATS, L.M. THOMPSON and W.R. WILCOX. Bisindolylmaleimide I suppresses fibroblast growth factor-mediated activation of Erk MAP kinase in chondrocytes by preventing Shp2 association with the Frs2 and Gab1 adaptor proteins. Journal of Biological Chemistry. Bethesda, USA: Amer. Soc. Biochem. Mol., 2006, vol. 282, No 5, p. 2929-2936. ISSN 0021-9258. Available from: https://dx.doi.org/10.1074/jbc.M606144200.

Basic information

• Original name: Bisindolylmaleimide I suppresses fibroblast growth factor-mediated activation of Erk MAP kinase in chondrocytes by preventing Shp2 association with the Frs2 and Gab1 adaptor proteins.
• Name in Czech: Bisindolylmaleimide I suppresses fibroblast growth factor-mediated activation of Erk MAP kinase in chondrocytes by preventing Shp2 association with the Frs2 and Gab1 adaptor proteins.
• Authors: KREJČÍ, Pavel (203 Czech Republic, guarantor, belonging to the institution), B. MASRI (840 United States of America), L. SALAZAR (840 United States of America), C. FARRINGTON-ROCK (840 United States of America), H. PRATS (840 United States of America), L.M. THOMPSON (840 United States of America) and W.R. WILCOX (840 United States of America).
• Edition: Journal of Biological Chemistry, Bethesda, USA, Amer. Soc. Biochem. Mol. 2006, 0021-9258.

Other information

• Original language: English
• Type of outcome: Article in a journal
• Field of Study: 30105 Physiology
• Country of publisher: United States of America
• Confidentiality degree: is not subject to a state or trade secret
• WWW: URL
• Impact factor: Impact factor: 5.808
• Organization unit: Faculty of Science
• Doi: http://dx.doi.org/10.1074/jbc.M606144200
• UT WoS: 000243793900019
• Keywords in English: TYROSINE KINASE; PC12 CELLS; TRANSCRIPTIONAL ACTIVATION; POTENT INHIBITORS; ENDOTHELIAL-CELLS; FGF RECEPTORS

Abstract

Fibroblast growth factors (FGFs) inhibit chondrocyte proliferation via the Erk MAP kinase pathway. Here, we explored the role of protein kinase C in FGF signaling in chondrocytes. Erk activity in FGF2-treated RCS (rat chondrosarcoma) chondrocytes or human primary chondrocytes was abolished by the protein kinase C inhibitor bisindolylmaleimide I (Bis I). Bis I inhibited FGF2-induced activation of MEK, Raf-1, and Ras members of Erk signaling module but not the FGF2-induced tyrosine phosphorylation of Frs2 or the kinase activity of FGFR3, demonstrating that it targets the Erk cascade immediately upstream of Ras. Indeed, Bis I abolished the FGF2-mediated association of Shp2 tyrosine phosphatase with Frs2 and Gab1 adaptor proteins necessary for proper Ras activation. We also determined which PKC isoform is involved in FGF2-mediated activation of Erk. When both conventional and novel PKCs expressed by RCS chondrocytes ( PKC alpha, -gamma, -delta, and -is an element of) were down-regulated by phorbol ester, cells remained responsive to FGF2 with Erk activation, and this activation was sensitive to Bis I. Moreover, treatment with PKC lambda/xi pseudosubstrate lead to significant reduction of FGF2-mediated activation of Erk, suggesting involvement of an atypical PKC.

Links

• MSM0021622415, plan (intention): Name: Molekulární podstata buněčných a tkáňových regulací

Investor: Ministry of Education, Youth and Sports of the CR, Molecular basis of cell and tissue regulations