Mitogen-activated protein (MAP) kinases (EC 22.214.171.124) are serine/threonine-specific protein kinases that respond to extracellular stimuli (mitogens) and regulate various cellular activities, such as gene expression, mitosis, differentiation, and cell survival/apoptosis.
MAPK is involved in the action of most nonnuclear oncogenes. It is responsible for cell response to growth factors such as BDNF or nerve growth factor.
Extracellular stimuli lead to activation of a MAP kinase via a signaling cascade ("MAPK cascade") composed of MAP kinase, MAP kinase kinase (MKK or MAP2K), and MAP kinase kinase kinase (MKKK or MAP3K, EC 126.96.36.199).
MAP kinase activation
MAP kinase kinase kinase
(MAP3K or MKKK)
MAP kinase kinase
(MAP2K or MKK)
A MAP3K that is activated by extracellular stimuli phosphorylates a MAP2K on its serine and threonine residues, and then this MAP2K activates a MAP kinase through phosphorylation on its serine and tyrosine residues. This MAP kinase signaling cascade has been evolutionarily well-conserved from yeast to mammals.
To date, six distinct groups of MAPKs have been characterized in mammals:
c-Jun N-terminal kinases (JNKs), (MAPK8,MAPK9,MAPK10) also known as stress-activated protein kinases (SAPKs).
p38 isoforms. (MAPK11, MAPK12(= ERK6), MAPK13, MAPK14) Both JNK and p38 signaling pathways are responsive to stress stimuli, such as cytokines, ultraviolet irradiation, heat shock, and osmotic shock, and are involved in cell differentiation and apoptosis.
ERK5. ERK5 (MAPK7), which has been found recently, is activated both by growth factors and by stress stimuli, and it participates in cell proliferation.
ERK3/4. ERK3 (MAPK6) and ERK4 (MAPK4) are structurally related atypical MAPKs posses SEG motif in activation loop and displaying major differences only in the C-terminal extension. ERK3 and ERK4 mostly cytoplasmic protein which binds, translocates and activates the MK5 (PRAK, MAP2K5). ERK3 is known as an unstable unlike ERK4 which is relativily stable.
ERK7/8. (MAPK15) This is newest member of MAPKs and behaves like atypical MAPKs. It possesses a long C terminus similar to ERK3/4.
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Animal intercellular signaling peptides and proteins