The Role of Tpl2 Protein Kinase in Carcinogenesis and Inflammation

The mitogen activated protein kinase (MAPK) cascade is a family of serine-threonine protein kinases controlling a vast array of cellular responses. Among the oldest signaling pathways known, the MAPK cascade is evolutionarily conserved, being found in species ranging from yeast to humans (Widmann et al., 1999). All eukaryotic cells possess multiple MAPK signaling pathways. In mammals, four major subfamilies (termed classical MAPKs) have been identified including extracellular signal-regulated kinase 1/2 (ERK1/2), c-jun Nterminal protein kinases (JNK/SAPK), p38 isoforms (p38 , , , or ), and ERK5 (Dhanasekaran and Johnson, 2007). These multiple parallel MAPK cascades all operate through a three tiered system characterized by consecutive phosphorylation events. Each of the pathways is equipped to respond to a remarkably diverse array of stimuli, including cytokines, growth factors, irradiation, hormones, injury, and stress (Cargnello and Roux, 2011). The binding of stimuli to receptors triggers the initial phosphorylation events. These events transform inactive MAP3K into active MAP3K. Subsequently, active MAP3K phosphorylates, and thereby activates, downstream MAP2K (MEK) proteins. The active MAP2K proteins then phosphorylate MAPK (ERK) molecules. These MAPK proteins then regulate the transcription of a diverse group of genes involved in inflammation, cell survival, cell division, development, metabolism, differentiation, motility, and repair (Cargnello and Roux, 2011).