MAPK Signaling Pathway

The mitogen-activated protein kinase (MAPK) family is a group of serine/threonine kinases that mediate intracellular signaling. The MAPK pathways are activated by diverse extracellular and intracellular stimuli including peptide growth factors, cytokines, hormones, and various cellular stressors such as oxidative stress and endoplasmic reticulum stress. These signaling pathways regulate a variety of cellular activities including proliferation, differentiation, survival, and death.

Six subfamilies of MAPKs have been extensively characterized in mammalian cells: ERK1/2, JNKs, ERK 3, p38s, ERK5 and ERK 7/8. Transmission of signals is normally achieved by sequential phosphorylation and activation of the components specific to a respective cascade. All MAPK cascades comprise several molecular intermediaries at sequential level, which become activated in response to a broad panel of intra- and extra-cellular stimuli. They are typically organized in a three-kinase architecture consisting of a MAPK, a MAPK activator (MEK, MKK, or MAPK kinase), and a MEK activator [MEK kinase (MEKK)].

Deviation from the strict control of MAPK signaling pathways has been implicated in the development of many human diseases including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and various types of cancers. Persistent activation of the JNK or p38 signaling pathways has been suggested to mediate neuronal apoptosis in AD, PD, and ALS; whereas the ERK signaling pathway plays a key role in several steps of tumorigenesis including cancer cell proliferation, migration, and invasion.