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The Ras signaling pathway links the signals from growth factor receptors with the activation of the MAPK kinase cascade of phosphorylation leading to cell growth and differentiation. External stimuli, such as endotoxins, UV irradiation, heat, and hyperosmolarity, induce an array of cellular responses that culminate with gene expression, ultimately dictating an adaptation to the new environment. The ultimate cellular response to environmental stress is cell death or apoptosis. This pathway is regulated by Rac1 and Cdc42 which link Jun Kinases (JNKs), such as p38. JNK is a c-Jun kinase that was also identified as SAPK1 and MAPKp49. JNK contains homology with the MAP/ERK family of kinases, and contains an N-terminal ATP-binding site and two autophosphorylation “TXY” sites. JNKK1/MEKK4/SEK1 is a dual-specificity kinase activated by conditions of cellular stress, such as heat shock and hyperosmolarity. JNKK1 phosphorylates JNK and p38 but not the ERK MAP kinases. Active JNK and p38 phosphorylate multiple transcription factors that induce expression of genes, such as proinflammatory cytokines.
