The R T K R A S M E K Signaling Pathway By Lenard Tardio
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The RTK RAS MEK signaling pathway begins when a ligand binds to a receptor tyrosine kinase (RTK), causing it to dimerize and autophosphorylate. This creates binding sites for the adaptor protein Grb2 and associated protein SOS. The Grb2-SOS complex activates RAS via catalyzing GDP-GTP exchange. Activated RAS recruits RAF to the membrane where it is activated. RAF then phosphorylates MEK, which phosphorylates ERK. ERK phosphorylates transcription factors like ELK-1, leading to expression of genes involved in growth responses. Activated ELK-1 also stimulates a phosphatase to deactivate ERK.
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The R T K R A S M E K Signaling Pathway By Lenard Tardio
- 1. The RTK RAS MEK Signaling Pathway Cytoplasm Extracellular RTK receptors are present in the membrane as monomers Dimerization of the receptor occurs after binding of a bivalent ligand Kinase activity is initiated when the two domains are in close contact allowing for trans-autophosphorilation P P Autophosphorilation sites act as binding sites for signaling proteins The SH2 domain of the adaptor protein Grb2, binds to the phosphorilated tyrosine residues on the RTK Grb2 The SOS protein then binds to the SH3 domain of Grb2. SOS Grb2-SOS The Grb2-SOS complex activates RAS by catalyzing the GTP-GDP exchange Activated RAS starts a MAP Kinase cascade by recruiting the protein RAF to the membrane where it is activated. RAS GDP GTP RAF The MAPKKK RAF, phosphorilates the MAPKK MEK MEK MEK MEK phosphorilates the MAPK ERK ERK ERK ERK phosphorilates transcription factors such as ELK-1 ELK-1 ELK-1 Phosphorilated ELK-1 transcribes genes such as Fos and Jun which are involved in the growth response. Activated ELK-1 stimulates the expression of a gene that encodes a MAPK phosphatase (MKP-1) which deactivates the MAPK ERK. MKP-1 ERK Abbreviation Key: RTK: Receptor protein-tyrosine kinase SH2: Src-homology 2 SH3: Src-homology 3 Grb2: Growth factor receptor-bound protein 2 SOS: Son of sevenless GTP: Guanosine triphosphate GDP: Guanosine diphosphate RAS: Rat sarcoma RAF: proto-oncogene c-RAF ERK: Extracellular-signal-regulated kinases ELK-1: E twenty-six (ETS)-like transcription factor 1 MKP-1: Mitogen-activated protein kinase phosphatase MEK: Dual specificity mitogen-activated protein kinase kinase MAPK: Mitogen-activated protein kinase MAPKK: Mitogen-activated protein kinase kinase MAPKKK: Mitogen-activated protein kinase kinase kinase P: Phosphate Sources: Lecture 5 slides Gerald Karp’s Cell and molecular biology, fifth edition Youtube: www.youtube.com/watch?v=r7GoZ9vFCY8