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MAP Kinase Signaling Pathways


Mitogen-activated protein kinases (MAPKs) are serine-threonine kinases that mediate intracellular signaling. The multifunctional mitogen-activated protein kinase (MAPK) signaling system consists of separate pathways that function to control a number of different cellular processes such as gene transcription, metabolism, motility, cell proliferation, apoptosis, synaptic plasticity and long-term memory. These different downstream effectors are activated by the final MAPK components associated with the three main signaling pathways:

Extracellular-signal-regulated kinase (ERK) pathway
c-Jun N-terminal kinase (JNK) pathway
p38 pathway

Each MAPK pathway contains a three-tiered kinase cascade comprising a MAP kinase kinase kinase (MAPKKK, MAP3K, MEKK or MKKK), a MAP kinase kinase (MAPKK, MAP2K, MEK or MKK) and the MAPK. This three-tier module mediates ultrasensitive switch-like responses to stimuli. These cascade protein kinase along with other functional components such as receptors, transducers, scaffolding protein and target protein form an extensive mitogen-activated protein kinase (MAPK) signaling toolkit, Specific components from this toolkit are then assembled into the different signaling pathways (Figure 1).

Transducers MAPKKK MAPKK MAPK Effectors Cellular
responses
ERK pathway  SOS Grb2  Ras Raf-1,A-Raf,B-Raf MEK1/2 ERK1/2 Ets,Elk1,SAP1,cPLA2 JNK pathway  Cdc42 Rac Rho MEKK1-4,MLK1-3,TAK1,
ASK1/3,TPL-2
MEK4/7 JNK1-3 c-Jun, Jun-B, Jun-D
ATF2, Elk1
p38 pathway Cdc42 Rac TAK1 MEK3 p38α/β/γ/δ ATF2, Ets, MEF2,
SAP1,MAPKAP2

Figure 1. Organization of the main mitogen-activated protein kinase (MAPK) signaling pathways.

The MAPK signaling cascades have been extensively studied over the past two decades and showed to operate in a large number of cells and conditions. The signal starts when a signaling molecule binds to the receptor on the cell surface and ends when the DNA in the nucleus expresses a protein and produces some change in the cell. Transmission of signals via these cascades is usually initiated by activation of a small G protein (e.g., Ras) or by activating interaction of upstream components of the cascade with adaptor proteins. Then, the signals are further transmitted downstream the cascade by cytosolic protein kinases that are organized in generally three tiers. The kinases in each tier phosphorylate and activate the kinases located in their downstream tier to allow a rapid and regulated transmission of the signals to various targets of the cascades. About 70 genes are known today to encode for close to 200 distinct components that compose the entire MAPK system. This multiplicity of components allows the extended specificity and tight regulation, which are hallmarks of these cascades (Table 1).

Research shows that MAPKs signaling pathway is highly conserved in cells through evaluation. Now several parallel MAPKs signaling pathways are existing in both unicellular lower eukaryote and higher mammal cells. Different extracellular stimuli transducing through different MAPKs pathways. These signal interact with each other and regulate each other to regulate different cell biological reactions.

Table 1.  Mitogen-activated protein kinase (MAPK) signaling toolkit

  Erk JNK P38
Transducer GCK, GLK, HPK1, MST1, SOS, Rac, Ras, cdc42, Rac
MAPKKKs Raf-1, B-Raf, PAK MEKK1,MEKK2,MEKK3,MEKK4
MLK1,MLK2,MLK3
ASK1,ASK3
TAK1, Tpl2
TAK
MAPKKs MEK 1, MEK2, MEK 5 MEK 4, MEK7 MEK 3
MAPKs Erk1,Erk2,Erk5,Erk7,Erk8 JNK1,JNK2,JNK3 P38α,P38β,P38γ, P38δ
Scaffolding proteins KSR1, KSR 2
MP-1
β-arrestin 1/2
JIP-1,JIP-2,JIP-3
β-arrestin 2
JIP-2, JIP-4
OSM
Target proteins ATF2, Cytoplasmic PLA2, ETS, Elk1, c-Jun, Jun-B, Jun-D, MEF2, MSK1,2, SAP-1
Phosphatases MKP-1,MKP-2,MKP-3,MKP-4,MKP-5
VHR, hVH3/B23 hVH5/M3/6, PAC1, Pyst2, STEP

Reference:

1. Keshet Y, Seger R. The MAP kinase signaling cascades: a system of hundreds of components regulates a diverse array of physiological functions[J]. MAP Kinase Signaling Protocols: Second Edition, 2010: 3-38.
2. Zhang W, Liu H T. MAPK signal pathways in the regulation of cell proliferation in mammalian cells[J]. Cell research, 2002, 12(1): 9-18.
3. Seger R, Krebs E G. The MAPK signaling cascade[J]. The FASEB journal, 1995, 9(9): 726-735.
4. Jeffrey K L, Camps M, Rommel C, et al. Targeting dual-specificity phosphatases: manipulating MAP kinase signalling and immune responses[J]. Nature reviews Drug discovery, 2007, 6(5): 391-403.
5. Cobb M H. MAP kinase pathways[J]. Progress in biophysics and molecular biology, 1999, 71(3): 479-500.
6. Pearson G, Robinson F, Beers Gibson T, et al. Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions 1[J]. Endocrine reviews, 2001, 22(2): 153-183.
7. Pritchard A L, Hayward N K. Molecular pathways: mitogen-activated protein kinase pathway mutations and drug resistance[J]. Clinical Cancer Research, 2013, 19(9): 2301-2309.
8. Kim E K, Choi E J. Pathological roles of MAPK signaling pathways in human diseases[J]. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease, 2010, 1802(4): 396-405.
9. Zhang Y, Dong C. Regulatory mechanisms of mitogen-activated kinase signaling[J]. Cellular and molecular life sciences, 2007, 64(21): 2771-2789.

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