title: 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.
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 (PKCalpha, -gamma, -delta, and -epsilon) 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 PKClambda/zeta pseudosubstrate lead to significant reduction of FGF2-mediated activation of Erk, suggesting involvement of an atypical PKC.
authors.affiliation: Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA. pavel.krejci@cshs.org
authors.forename: Pavel
authors.initials: P
authors.lastname: Krejci
authors.forename: Bernard
authors.initials: B
authors.lastname: Masri
authors.forename: Lisa
authors.initials: L
authors.lastname: Salazar
authors.forename: Claire
authors.initials: C
authors.lastname: Farrington-Rock
authors.forename: Herve
authors.initials: H
authors.lastname: Prats
authors.forename: Leslie Michels
authors.initials: LM
authors.lastname: Thompson
authors.forename: William R
authors.initials: WR
authors.lastname: Wilcox
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D045744:Cell Line, Tumor; D019902:Chondrocytes / Q000187:drug effects / Q000502:physiology*; D006224:Cricetinae; D003412:Cricetulus; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005346:Fibroblast Growth Factors / Q000502:physiology*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D008301:Maleimides / Q000494:pharmacology*; D008565:Membrane Proteins / Q000378:metabolism*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*; D051381:Rats
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004791:Enzyme Inhibitors; C106534:FRS2 protein, human; C098587:GAB1 protein, human; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins; D008301:Maleimides; D008565:Membrane Proteins; D005346:Fibroblast Growth Factors; D048049:Extracellular Signal-Regulated MAP Kinases; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases; C516727:Ptpn11 protein, rat; C070515:bisindolylmaleimide I