23.3: MAPK Signaling Cascades

Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP Kinase, the final kinase of the cascade. Activated MAP Kinase now phosphorylates downstream substrates, including transcription factors, and facilitates gene expression changes to elicit an appropriate cellular response. The three types of MAPK pathways in mammals are:

• ERK (Extracellular signal-regulated kinases).
• JNK (Jun amino-terminal kinases).
• P38/SAPKs (Stress-activated protein kinases).

The classical ERK pathway is activated when growth factors or mitogens bind and activate the RTKs, GPCRs, or integrins to initiate cell growth and differentiation. Environmental stresses such as radiation, oxidative stress, and DNA damage induce JNK family activation and cause cell death and inflammation. Alternately, P38 pathways are also activated in response to environmental stresses and cytokines, promoting inflammation, cell death, cell differentiation, and cell cycle regulation.

Eukaryotes use all three MAP Kinase modules and elicit different responses in the cell. With the help of scaffolds, they often share the same kinases and activate different effector proteins without crosstalk between the signaling pathways. Scaffold proteins channel the incoming signal to the correct MAPK module, ensuring signal specificity, thereby eliciting an appropriate response. The scaffold protein also increases the signal transduction by localizing or orienting the protein complexes near their substrates. For example, once the Ras is activated, the kinase suppressor of Ras or the KSR protein recruits MEK1/2 to the plasma membrane and places it next to the Raf, activating downstream proteins ERK1 and ERK2. KSR is a pathway-specific scaffold protein that avoids cross-talk between parallelly occurring MAPK modules. The combined effect of localization of adaptor proteins, substrate, and associated kinases enhances signal relay. Activated MAP kinase phosphorylates its cytoplasmic substrates or is transported to the nucleus to activate transcription factors such as c-Jun and c-Fos, eventually triggering the cyclin D1 gene and promoting the cell cycle progression.

Mitogen-activated protein kinase or MAPK pathways relay signals downstream of RTKs to activate transcription factors.

In the Ras-MAPK signaling pathway, Raf, the initial kinase of this pathway, binds the 14-3-3 protein dimer and remains inactive in the cytosol.

Mitogen binding on the RTKs activates Ras GTP, which then binds the Raf/14-3-3 complex.

Phosphorylation of multiple sites on Raf disassembles the complex allowing Raf to dimerize with a nearby phosphorylated monomer.

The dimeric Raf now phosphorylates and activates another kinase, MEK , which in turn phosphorylates the cascade's final kinase, ERK.

The activated ERK is transported to the nucleus to phosphorylate transcription factors such as c-Jun and c-Fos and initiate cellular processes such as cell proliferation, survival, differentiation, or apoptosis.