Use of inhibitors in the study of MAP kinases.
The mitogen-activated protein (MAP) kinases are ubiquitous intracellular signaling proteins that respond to a variety of extracellular signals and regulate most cellular functions including proliferation, apoptosis, migration, differentiation, and secretion. The four major MAP kinase family members, which include the ERK1/2, JNK, p38, and ERK5 proteins, coordinate cellular responses by phosphorylating and regulating the activity of dozens of substrate proteins involved in transcription, translation, and changes in cellular architecture. Uncontrolled activation of the MAP kinases has been implicated in the initiation and progression of a variety of cancers and inflammatory disorders. As such, the ability to manipulate the activity of MAP kinase proteins with specific pharmacological inhibitors has received much attention as research tools for understanding basic mechanisms of cellular functions and for clinical tools to treat diseases. A variety of pharmacological inhibitors have been developed to selectively block MAP kinases directly or indirectly through targeting upstream regulators. This chapter will provide an overview of some of the current inhibitors that target MAP kinase signaling pathways and provide methodology on how to use selective MAP kinase inhibitors and immunoblotting techniques to monitor and quantify phosphorylation of MAP kinase substrates.
Burkhard
Kimberly
K
Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD, USA.
Shapiro
Paul
P
D000818:Animals; D000906:Antibodies / Q000276:immunology; D000918:Antibody Specificity; D003720:Densitometry; D004591:Electrophoresis, Polyacrylamide Gel; D004789:Enzyme Activation / Q000187:drug effects; D057075:Enzyme Assays / Q000379:methods*; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D010750:Phosphoproteins / Q000276:immunology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D013379:Substrate Specificity
D000906:Antibodies; D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; D020928:Mitogen-Activated Protein Kinases
J Pharmacol Exp Ther. 2005 Dec;315(3):971-9
16002463
Curr Opin Cell Biol. 2009 Apr;21(2):317-24
19217767
J Biol Chem. 1998 Jul 17;273(29):18623-32
9660836
Semin Oncol. 2006 Aug;33(4):369-85
16890793
Expert Opin Emerg Drugs. 2006 Nov;11(4):651-64
17064224
J Med Chem. 2002 Jul 4;45(14):2994-3008
12086485
Clin Cancer Res. 2008 Jan 15;14(2):342-6
18223206
FEBS Lett. 1995 May 8;364(2):229-33
7750577
J Med Chem. 2005 Jul 14;48(14):4586-95
15999996
Biochem Biophys Res Commun. 2008 Dec 5;377(1):120-5
18834865
Annu Rev Immunol. 2004;22:247-306
15032571
Ann Med. 2006;38(3):200-11
16720434
FEBS Lett. 2001 Jul 27;502(1-2):21-4
11478941
Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):7686-9
7644477
Biochem J. 2003 Apr 1;371(Pt 1):199-204
12534346
Curr Opin Investig Drugs. 2008 Jun;9(6):614-30
18516761
Nat Struct Biol. 2002 Apr;9(4):268-72
11896401
Proc Natl Acad Sci U S A. 2001 Nov 20;98(24):13681-6
11717429
J Oncol Pharm Pract. 2007 Dec;13(4):199-205
18045779
Adv Cancer Res. 1998;74:49-139
9561267
Chembiochem. 2005 Mar;6(3):481-90
15742384
Expert Rev Anticancer Ther. 2006 Mar;6(3):313-9
16503848
Nat Med. 1999 Jul;5(7):810-6
10395327
Biochem J. 2000 Oct 1;351(Pt 1):95-105
10998351
Semin Oncol. 2001 Oct;28(5 Suppl 16):86-93
11706400
Structure. 1998 Sep 15;6(9):1117-28
9753691
Nature. 1994 Dec 22-29;372(6508):739-46
7997261