MAP Kinase Signaling – Ribosome Studio (2020)

In order to learn a subject matter that has detailed sequential stages, it is best to consult multiple resources that tell the same story with their own twists. Mitogen Activated Protein Knase (MAPK) signaling pathway is one of these important subjects. Here as part of the molecular nature series you can find three such narratives focusing on MAPK signaling. The first and the main video was produced by the Ribosome Studio commissioned by of the Applied Sciences/ZHAW Life Sciences Pharmaceutical Biotechnology Program of Zurich University. Using molecular animations it very effectively visualizes the dynamics of the intracellular signaling that begins with the 53 aminoacid long Epidermal Growth Factor (EGF) peptide binding to the Epidermal Growth Factor Receptor (EGFR) which is a receptor with a tyrosine kinase domain. Once EGF binds to EGFR it induces dimerization with another EGFR member such as the HER2 and initiates phosphorylation of each other which as also called transphosphorylation or trans-autophosphorylation if the dimer partner is the same. Activation of the EGFR dimer recruits the adaptor protein Growth Factor Receptor-Bound protein 2 (GRB2) and the guanine nucleotide exchange factor called Son of Sevenless 1 (SOS1). After this GRB2/SOS1 recruitment step the MAPK kinase cascade is initiated.

At the beginning, the usage of a diverse set of gene name acronyms can be confusing for the learners. At this stage the second narrative from Dr. Susannah Hannaford of the University of Puget Sound comes to the rescue. Dr. Hannaford’s lecture beautifully summarizes the general categorization of the MAP Kinase cascade as MAPKKK > MAPKK > MAPK. This hierarchical generalization forms the overall pattern of Extracellular Signal Regulated Kinase 1 and 2 (ERK1/2), c-Jun-amino-terminal kinase (JNK), p38 mitogen-activated protein kinase (p38) and Extracellular Signal Regulated Kinase 5 (ERK5) pathways.

The third source in this series is a three part lecture by Dr. Elliot Nicholson. It is quite detailed and deliberately repetitious (that’s how most of us learn best) with re-drawing of key enzymes and proteins involved. So here you can see the first part as a teaser of what’s coming. Throughout the lecture, Dr. Nicholson introduces some side information that sparks curiosity to branch out and learn more. For instance in the third part of the lecture series, the farnesyl group derived from concatenations of isoprene residues in the RAS protein is one such detail that is rarely (almost never) mentioned in explanations of the MAPK signaling. The lipophilic farnesyl group in RAS enables the anchoring of the protein to the cytosolic side of the plasma membrane. This is quite intriguing since the MAPK signaling is also very well conserved in plants. In terrestrial plants protein farnesylation and biosynthesis of its isoprene precursor are associated with heat, drought and oxidative stress. Proteins that are post-translationally modified by prenylation carry a characteristic CaaX box motif in their C-terminus.

MAPK signaling cascade is one of the key subjects in understanding causes and treatment of cancer since any misregulation in this complex network of protein kinases leads to runaway cell proliferation which is a hallmark of tumor forming cells.