1. Chemical Biology Tools for Regulating RAS Signaling Complexity in Space and Time 
Hilde van Hattum, Herbert Waldmann 
Chemistry & Biology 
Volume 21, Issue 9, Pages (September 2014)
DOI: /j.chembiol
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2. Chemistry & Biology 2014 21, 1185-1195DOI: (10. 1016/j. chembiol. 2014
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3. Figure 1 Schematic Representation of the RAS Activation Cycle
Inactive GDP-bound RAS is activated via signals from extracellular stimuli by means of GEFs, like SOS1 and 2, which induce GTP binding and stimulate downstream signaling. GAPs, including NF1 and p120, subsequently induce GTP hydrolysis and thereby terminate RAS signaling.
Chemistry & Biology  , DOI: ( /j.chembiol )
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4. Figure 2
Simplified Overview of Selected Signaling Pathways Emerging from RAS Proteins
RAS activates, among others, the RAF/MEK/ERK and the PI3K/PDPK1/AKT pathway. RAS activates RAF, which phosphorylates MEK1/2. Subsequently, MEK1/2 phosphorylates and activates the MAPK kinases ERK1/2, which results in the activation of a group of effector proteins, including ETS proteins, such as ELK1. Furthermore, RAS-GTP activates PI3Ks, which recruit the AKT complex, through PDK1, followed by the activation of mTOR. Phosphorylated PI3K also activates Rac, which influences cytoskeleton reorganization. Crosstalk between the pathways takes place at AKT, which stimulates RAS and mTOR that downregulates ERK1/2.
Chemistry & Biology  , DOI: ( /j.chembiol )
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5. Figure 3
The HRV of the Different Isoforms of RAS, which Define the Plasma Membrane Targeting Region
All proteins are farnesylated and methylated on the C terminus. HRAS, KRAS4A, and NRAS are additionally palmitoylated. KRAS contains a poly-basic lysine stretch that mediates the interaction between the negatively charged inner leaflet of the plasma membrane.
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6. Figure 4 Schematic Representation of KRAS Distribution in Space
KRAS is farnesylated in the ER and transported to the recycling endosomes by PDEδ, where its release is aided by ARL. Subsequently, the ensodomes fuse with the plasma membrane. Release from the membrane occurs either via spontaneous release or via endocytosis. The pool of free KRAS is again transported to the recycling endosomes by PDEδ.
Chemistry & Biology  , DOI: ( /j.chembiol )
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7. Figure 5
Schematic Representation of H- and N-RAS–Depicted by One RAS Protein—Distribution in Space
RAS is farnesylated in the ER and transported by PDEδ to the Golgi, where it is palmitoylated. RAS travels to the plasma membrane via vesicular transport, where it is depalmitoylated. The protein is spontaneously released from the membrane and is transported to the Golgi by PDEδ.
Chemistry & Biology  , DOI: ( /j.chembiol )
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8. Figure 6 Chemical and Enyzymatic Methods to Obtain Lipidated Proteins
(A) Enzymatic approach.
(B) MIC ligation.
(C) Native chemical ligation.
Chemistry & Biology  , DOI: ( /j.chembiol )
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9. Figure 7 Structures of Inhibitors that Interfere with RAS Signaling
Chemistry & Biology  , DOI: ( /j.chembiol )
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10. Figure 8 Structures of Inhibitors Targeting RAS
Chemistry & Biology  , DOI: ( /j.chembiol )
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