MAPK Signaling Cascade
MAPKs (Mitogen-activated protein (MAP) kinases) are serine/threonine-specific protein kinases that
respond to extracellular stimuli (mitogens) and regulate various cellular activities, such as gene
expression, mitosis, differentiation, proliferation, and cell survival/apoptosis. The MAPKs most
intensely studied are ERK (Extracellular Signal-Regulated Kinase) 1/2, the p38 kinase (p38-Alpha,
Beta, Gamma and Delta), JNK (c-Jun N-terminal kinase) 1, 2, 3 and ERK5. As part of a three kinase
module, MAPKs are phosphorylated and activated by MKKs (MAPK Kinases). MKKKs (MAPK kinase kinases)
also phosphorylate and activate MKKs. In addition, many MKKKs can phosphorylate and activate more than
one class of MKKs for example MKKK, MEKK3, can activate both p38 and ERK5.
In addition, scaffold proteins such as kinase suppressor of Ras, Beta-arrestin and the JNK-interacting
proteins organize MAPK modules in complexes with other proteins, control trafficking and sub cellular
location, and duration of MAPK signaling. Thus, the combination of differential control of MKKK
activation and the organization of signaling complexes by scaffolding proteins provides a
combinatorial diversity for the integration of MAPK networks in the cellular response to stimuli such
as cytokines, growth factors, antigens, toxins, pharmacological drugs and stresses such as temperature
change and irradiation, and changes in cell shape, cell–cell interaction and extracellular matrix
composition.
Role of MAPKs in many critical responses is required for cellular homeostasis. Loss of fine control of
MAPK regulation results in mutation or changes in expression of proteins regulating MAPK signaling,
such as activating Ras or Raf mutations, epidermal growth factor receptor over expression or
inactivation of MKK4, contributing to cancer. Changes in MAPK regulation also contribute to
inflammation and neurodegeneration and many other diseases. For these reasons, the MAPKs have been a
focus of intense drug discovery programs by both academic laboratories and the
biotechnology/pharmaceutical industry.
|
|