- MAPK/ERK signaling pathway
(MAPK: Mitogen activated protein kinases, ERK: Extracellular signal regulated kinases)
Other name: Ras – Raf – MEK – ERK pathway
- This pathway contains a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell.
- The signal for MAPK pathway 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, such as cell division.
How the proteins in this pathway communicate each other?
It is done by adding phosphate groups to a neighboring protein, which acts as an “on” or “off” switch.
MAPK signaling cascade
The name MAP-kinase cascade is given in honor of the final kinase in the chain MAP-kinase
Step 1: MAPK signaling begins with the activation of the protein Ras by receptor tyrosine kinases.
Step 2: Activated Ras recruit soluble Raf in the cytoplasm to the membrane and activates protein kinase activity of Raf kinase.
Activation of Raf Kinase
- The mechanism for activating Raf differs from that used to activate many other protein kinases including MEK and MAP kinase.
- In a resting cell prior to hormonal stimulation, Raf is present in the cytosol in a conformation in which the N-terminal regulatory domain is bound to the kinase domain, thereby inhibiting its activity.
- The binding of Ras.GTP (which is anchored to the membrane) to the N-terminal domain of Raf relieves the inhibition of Raf’s kinase activity.
Step 3: GTP hydrolysis leads to the dissociation of Raf from Ras.GDP
(Refer lecture on Ras protein to know how it happens)
Step 4: Raf kinase (serine –threonine selective kinases) phosphorylates and activates MEK (MEK1 and MEK2).
(Full activation is achieved through the phosphorylation of two serine residues; MEKs can be partially activated by phosphorylation at either site)
Step 5: MEK (serine/tyrosine/threonine kinase) phosphorylates and activates a mitogen-activated protein kinase (MAPK) or ERK.
Unlike MEK, significant ERK activation requires phosphorylation at both sites (Dual threonine and tyrosine residue phosphorylation)
Phosphorylation promotes not only the catalytic activity of MAP kinase but also its dimerization. The dimeric form of MAP kinase (but not the monomeric form) can be translocated to the nucleus, where it regulates the activity of many nuclear transcription factors.
Downstream signaling of ERK/MAPK pathway
The ERKs are proline-directed protein kinases, phosphorylating proline-neighboring serine or threonine residues.
- Phosphorylated ERK can directly and indirectly activate many transcription factors (Elk – 1, c-Myc, CREB, c – fos etc), altering their ability to control gene transcription and thereby causing a change in the pattern of gene expression.
- These transcription factors are often regulatory in nature and are located both in the cytoplasm and the nucleus.
Activation of MAP kinase following stimulation of a growth factor receptor (Example: EGFR) leads to phosphorylation and activation of two transcription factors: TCF and SRF. These associate into a trimeric complex that promotes transcription of various early-response genes
- In the cytosol, MAP kinase phosphorylates and activates another kinase, p90RSK (40S ribosomal protein S6 kinase) which translocates to the nucleus, where it phosphorylates a specific serine in SRF (serum response factor).
- Phosphorylated dimeric MAP kinase also translocates to the nucleus and directly phosphorylates specific serines in TCF (ternary complex factor).
Association of phosphorylated TCF with two molecules of phosphorylated SRF forms an active trimeric factor.
This trimeric factor binds to the serum response element (SRE) in the promoter region of target genes. Then they regulate the activity of many immediate early genes (for example c-fos) and thereby participate in cell cycle regulation, apoptosis, cell growth, and cell differentiation.
How the MAPK signaling cascades control cell cycle?
- Cdc25 activates cyclin dependent kinases by removing phosphate from residues in the Cdk active site.
- It is known to control the transitions from G1 to S phase and G2 to M phase.
- Erk1/2 can activate Cdc25 protein and in turn promote the cell cycle progression.
Role of MAPK signaling cascade in Oncogenesis
- ERK1/2 activation promotes metaplasia and tumor development by phosphorylating Bim and Bid and causing the proteasome degradation of Bim and the sequestration of Bad to the phosphoserine-binding proteins and, thereby, inhibiting apoptosis.
- In a separate pathway, ERK1/2 activation phosphorylates FOXO3a at Ser 294, Ser 344, and Ser 425 and facilitates FOXO3a-MDM2 interaction. This interaction enhances FOXO3a degradation through a MDM2-dependent ubiquitin-proteasome pathway, leading to tumor development.
Development and Differentiation control by MAPK pathway
- Signaling by receptor tyrosine kinases that activate the Ras/Raf/MAP kinase pathway regulates development and differentiation of many types of cells.
- Mainly through the activation of the signal transducers and activators of transcription proteins (STATs).