Functional Dichotomy of Protein Kinase C (PKC) in Tumor Necrosis Factor-α (TNF-α) Signal Transduction in L929 Cells

Abstract

Tumor necrosis factor-␣ (TNF-␣

Differential effects of NF-κB on apoptosis induced by DNA-damaging agents: the type of DNA damage determines the final outcome

“…TNF-a is a membrane-bound molecule that upon de novo synthesis is exported from the trans-Golgi network to the plasma membrane in a protein kinase C (PKC)-dependent manner (Lee et al, 2000;Abdel-Raheem et al, 2005). Once exposed to the plasma membrane, it can be sheded by different metalloproteinases belonging to the TNF-a-converting enzyme family (Mezyk et al, 2003), resulting in the release of soluble TNF-a.…”

Regulation of Protein Kinase C function by phosphorylation on conserved and non-conserved sites

“…It has also been reported that dephosphorylation of PKCs can occur at sites such as the A-loop and HM in response to stimuli such as Tumor Necrosis Factor-, which is likely to be a key step in turning off the signalling capacity of these kinases [75]. Prolonged PKC signalling that is promoted by phorbol esters or sustained DAG signalling results in downregulation of…”

“…Dephosphorylation of PKCs in cells was initially shown to be sensitive to okadaic acid, which implicated the PP2a-like phosphatases in this process [79,80,75]. More recent studies have identified an additional family of okadaic acidinsensitive phosphatases called PHLPPs that specifically dephosphorylate the HM (but not the TM) of PKCs upon prolonged phorbol ester treatment [81].…”

Ceramide regulates cellular homeostasis via diverse stress signaling pathways

“…[5][6][7][8][9][10][11] Ceramide activates a number of kinases ( Figure 1) including stress-activated protein kinases (SAPKs) such as the jun kinases (JNKs [25][26][27] ), kinase suppressor of Ras (KSR [28][29][30], and the atypical PKC isoform, PKC . [31][32][33] Conversely, ceramide can inhibit kinases such as the classical and novel PKC isoforms (eg PKC ␣ [14][15][16] ) and the PKB kinase, Akt. 29,[34][35][36] The mechanism of kinase inhibition appears to involve ceramide's ability to activate protein phosphatases (Figure 1 and Refs 16,17,[36][37][38][39].…”

“…12 Consistent with the notion that DAG and ceramide have counterbalancing effects, DAG can attenuate the effects of ceramide 13 and ceramide can antagonize DAG by inhibiting PKC. [14][15][16] An elegant homeostatic regulatory system is emerging with DAG as a growth positive regulator and ceramide as a negative growth regulator. Since each effector is able to transmodulate the signaling pathways regulated by the other, it is possible that net expression of DAG vs ceramide may create a sort of cellular rheostat.…”