Signal Transduction Inhibitors in Cellular Function
Signal transduction pathways mediate cell-cell interactions and integrate signals from the extracellular environment through specific receptors at the cell membrane. They play a pivotal role in regulating cellular growth and differentiation and in mediating many physiological and pathological processes, such as apoptosis, inflammation, and tumor development. The mitogenactivated protein kinases (MAPKs) constitute a cascade of phosphorylation events that transmit extracellular growth signals through membrane-bound Ras to the nucleus of the cell. In this chapter, detailed protocols for analyzing the kinase activities of the key components of the MAPKs pathway—MEK1, ERK1, JNK, and p38 MAPK—are described. A brief introduction to the chemical inhibitors to the MAPKs pathway is provided in the method section of each kinase assay. Inhibitors of other signaling pathways are summarized in Table 1 . The reporter assay of cyclin D1, a key downstream target gene of MAPKs pathway, is also described in detail. Table 1. Signal Transduction Pathways and Inhibitors
Signal Transduction Pathways | Inhibitors | References |
|---|---|---|
Tyrosine Kinase Growth Factor Receptors | ||
HER2/Neu inhibitor | Herceptin (anti-HER2 antibody) | (53,54) |
EGF receptors | IMC-C225 (anti-EGFR antidody) | (55,56) |
EGFR-Tyrosine kinase | ZD1839, pyridopyrimidines | (54,57,58) |
Ras Signaling | ||
Inhibitors of Ras farnesyltransferase FPP analogues | ||
CAAX peptide analogues | BZA-5B, L-739, Cys-4-ABA-Met FT1-276, SCH44342, SCH66336 | (57 –59) |
Bisubstrate inhibitors | BMS-182878, BMS-184467 | (57 –59) |
Inhibitors of the Raf protein kinases | ISIS5132, BAY43-9006 | (57 –59) |
Mitogen-Activated Protein Kinase Pathways | ||
Inhibitors of MEK | PD184352, PD098059, U0126, R009-22110 | (17,20,21 , 23 –27) |
Inhibitors of ERK1 and ERK2 | PD098059, E64D, calpeptin | (5,28) |
Inhibitors of JNKs | SB600125 | (33,34) |
Inhibitors of p38 kinases | SB203580, SB202190, SB242235, SB239063, SB220025, SB202474, SC68376, FR167653 | (36,37 , 39 –44,46) |
Inhibitors of PI3-Kinase Signaling Pathways | Wortmannin, LY294002 | (60,61) |
Protein Phosphatases Inhibitors Proteasome Inhibitors | Microcystines, calyculins, cantharidin | (67) |
Peptide aldehydes | ALLN, MG132, PSI, MG115 | (63) |
Peptide boronates | MG262 | (63) |
Nonpeptide inhibitors | Lactacystin | (63) |
DCI | 3,4-DCI | (63,64) |
Peptide vinyl sulfones | NLVS, YL3YS | (63) |
Epoxyketones | Epoxomicin, eponemycin, Ac-hFLFL-epoxide | (63,65) |
Bivalent inhibitors | Polyoxyethylene | (66,67) |
Natural compound inhibitors | TMC-95A, gliotoxin, EGCG | (63,68) |
Histone Deacetylase inhibitors | ||
Short-chain fatty acids | Butyrates | (70,75) |
Hydroxamic acids | Trichostatin A, oxamflatin | (73) |
Cyclic peptides | Trapoxin A, FR901228, apicidin | |
Benzamides | MS-27275 | (78,80) |
SIR2 inhibitors | Nicotinamide, splitomicin | (78,79) |
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