Apoptosis Intracellular Kinases

Intracellular signaling pathways regulate the decision of whether a cell lives or dies. While death ligands such as Fas and TNF-alpha bind to their receptors to promote caspase activation and cell death, anti-apoptotic ligands, such as growth factors, bind to cell surface receptors and activate intracellular kinases that promote cell survival. These kinases include PI 3-K, Akt/PKB, PKA, PKC, MEKs, ERK1/2, p90RSK, and p38 MAP kinases. Intracellular kinases ultimately activate or inhibit other cellular proteins involved in apoptosis, or transcription factors that inhibit the expression of pro-apoptotic proteins, or promote the expression of cell survival proteins. For example, activation of PI 3-K leads to the phosphorylation and activation of Akt/PKB resulting in the Akt-dependent phosphorylation and inhibition of pro-apoptotic molecules such as Bad, GSK-3, caspase-9, and the forkhead family of transcription factors (FKHR). Similarly, other intracellular kinases activate transcription factors such as CREB and STAT family members which induce the expression of Bcl-2 and Bcl-x_L, two Bcl-2 family members that protect the cell from apoptosis.