MAPK Pathway Signaling: A Case Study

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1. Describe MAPK pathway signaling (from the receptor activation to the gene transcription)
Overall, the extracellular mitogen binds to the membrane receptor. This allows RAS GTPase to swap its GDP for a GTP. It can now activate MAP3K (e.g., RAF), which activates MAP2K, which activates MAPK. MAPK can now activate a transcription factor, such as MYC.
In more details, receptor-linked tyrosine kinase as the epidermal growth factor (EGFR) is activated by extracellular ligand, epidermal growth factor (EGF). This activates the tyrosine kinase activity of the cytoplasmic domain of the receptor. The EGFR becomes phosphorylated on tyrosine residues. Next, GRB2 binds to the phosphotyrosine residues of the activated receptor. Then GRB2 binds to the guanine exchange factor SOS. When the GRB2-SOS complex docks to phosphorylated EGFR, SOS becomes activated. Activated SOS then promotes the removal of GDP from a member of the RAS. RAS can then bind GTP and become active. Activated RAS activates the protein kinase activity of RAF kinase. RAF kinase phosphorylates and activates MEK (MEK1 and MEK2). MEK phosphorylates and activates a mitogen-activated protein kinase (MAPK). MAPK can now activate a transcription factor, such as MYC.
2.
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What is paradoxical activation of MAPK signaling?
This is activation of MAPK signaling pathway as a consequence of using a first generation ATP-competitive RAF inhibitors in treatment of metastatic melanoma. These inhibitors can either inhibit or paradoxically activate MAPK signaling depending whether activation is by BRAF mutation or by an upstream event, such as RAS mutation or receptor tyrosine kinase activation. These RAF inhibitors inhibit ERK signaling in cells with mutant BRAF, but enhance signaling in cells with wild-type BRAF. This paradox promotes cellular proliferation and manifest clinically with progression of skin

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