c-Raf/MEK/ERK Pathway Controls Protein Kinase C-mediated p70S6K Activation in Adult Cardiac Muscle Cells

Abstract

Hypertrophic cardiac growth is a major compensatory response of the heart to an increased mechanical (hemodynamic) load in the form of either pressure or volume overload. Although this response is initially compensatory, a transition from this state to failure occurs when further growth of the heart is not sufficient to normalize the wall stress and maintain contractile function (1). Therefore, a major research interest in cardiovascular disease is to understand how the increase in hemodynamic load is transmitted intracellularly for mediating hypertrophic growth. Although the mechanical load appears to directly regulate the hypertrophic growth initiation, the signaling mechanism that connects load to such growth is not well understood.A major cellular event during cardiac hypertrophy is increased protein synthesis (1-5). Enhanced protein synthesis can occur via accelerated protein translation, increased biogenesis of translational components, or both. A significant amount of mRNA of vertebrate cells possesses a unique 5Ј-terminal oligopyrimidine (5Ј-TOP) 1 sequence in the 5Ј-untranslated region (5Ј-UTR), and these mRNA species generally code for specific ribosomal proteins (6, 7). Their translation is largely controlled via phosphorylation of the 40 S ribosomal S6 protein (S6 protein) at its C terminus (8) by p70/85 S6 kinase (S6K1) (9 -12). There are two isoforms of S6K1: the 70-kDa isoform was first isolated from mouse 3T3 cells (13), and the 85-kDa isoform of this kinase was then identified (14). The p85 isoform is expressed from the same transcript as the p70 isoform through an alternative translational initiation start site, which adds a 23-amino acid nuclear localization signal to the N terminus (15,16). Therefore, the 85-kDa isoform is predominantly in the nucleus, whereas the 70-kDa isoform is present mostly in the cytoplasm. Both the S6K isoforms are collectively called p70/85S6K, p70S6K, or S6K1 and have been shown to phosphorylate the S6 protein and mediate the biogenesis of the translational components, including several of the ribosomal proteins and elongation factors (12). The p85 isoform has been shown to have additional roles in translational control, G 1 to S phase transition, and increased DNA synthesis (17). Recent studies using S6K1 knockout mice (18) demonstrate no appreciable change in S6 protein phosphorylation, 5Ј-TOP mRNA translation, or cell growth, although these mice exhibited a small mouse phenotype. These studies (18) and other independent studies (19 -21) resulted in the discovery of another S6K (S6K2), which possesses 70% homology with the p70 isoform of

p38 mitogen-activated protein kinase contributes to cell cycle regulation by cAMP in FRTL-5 thyroid cells

“…We also exclude an effect of SB203580 on forskolin-stimulated S6K1 phosphorylation in FRTL-5 cells. A similar result was also reported in feline cardiomyocytes, where forskolin activates both p38 MAPKs and S6K1 (35). It has also been reported that a high concentration of SB203580 reduced the activity of c-Jun N-terminal kinases (JNKs) in rat ventricular myocytes and in transfected COS-7 cells (36, 37), but JNKs were not activated either by cAMP in FRTL-5 cells (11) or by IGF-I in human thyrocytes (38).…”

Phosphorylation of Eukaryotic Translation Initiation Factor 4B (EIF4B) by Open Reading Frame 45/p90 Ribosomal S6 Kinase (ORF45/RSK) Signaling Axis Facilitates Protein Translation during Kaposi Sarcoma-associated Herpesvirus (KSHV) Lytic Replication

“…4B, right panel). The minor inhibition of rpS6 phosphorylation by U1026 probably reflects the cross-talk between ERK/RSK and mTOR/ S6K signaling cascades (55)(56)(57). Interestingly, even a combination of rapamycin and U0126 did not inhibit eIF4B phosphorylation completely (Fig.…”

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