Compartmentalised MAPK Pathways

Contents

1 Introduction 206

1.1 The MEK/ERK Cascade 206

1.2 JNK Pathway 209

1.3 p38 Pathway 209

2 Specificity of MAPK Signalling 209

2.1 Receptor-Specific Pathways 209

2.2 Signalling Kinetics 210

2.3 Integration of Multiple Pathways 211

2.4 Tissue-Specific Downstream Effectors 211

3 Compartmentalisation of the MAPK Pathway 212

3.1 Plasma Membrane 212

3.2 Endosomes 214

3.3 Golgi and Endoplasmic Reticulum 215

4 Molecular Scaffolds 216

4.1 Kinase Suppressor of Ras 216

4.2 IQGAP1 218

4.3 MEK Partner-1 219

4.4 b-Arrestins 219

4.5 Similar Expression to FGF 220

5 MAPK as Drug Targets 220

5.1 MAPK and Oncogenes 220

5.2 MAPK and Inflammatory Diseases 223

5.3 Targeting the MAPK Pathway in Other Diseases 224

5.4 Future Direction for Therapies Directed Against the MAPK Cascade 225

6 Perspectives 227

References 229

Abstract The mitogen-activated protein kinase (MAPK) pathway provides cells with the means to interpret external signal cues or conditions, and respond accordingly. This cascade regulates many cell functions such as differentiation, proliferation and migration. Through modulation of both the amplitude and duration

D.B. Sacks

Brigham and Women's Hospital and Harvard Medical School, Thorn 530, 75 Francis St, Boston, MA 02115, USA [email protected]

E. Klussmann, J. Scott (eds.) Protein-Protein Interactions as New Drug Targets. 205 Handbook of Experimental Pharmacology 186,

© Springer-Verlag Berlin Heidelberg 2008

of MAPK signalling, cells can control their responses to the multiple activators of the pathway. In addition, recent work has highlighted the importance of the cellular compartment from which the signalling occurs. Cells have developed intricate systems that enable them to localise MAPK components to specific subcellular domains in response to a particular stimulus. Consequently, different factors can activate the same kinase in separate locations. Crucial to this ability are molecular scaffolds, which act as signalling modules for MAPKs, confining them to the desired compartment. The participation of the MAPK network in fundamental physiological processes, such as cell proliferation and inflammation, and the derangement of the homeostasis that occurs in disease processes, renders MAPK a highly desirable target for therapeutic intervention. As we enhance our comprehension of scaffolds and other regulatory molecules, novel targets for drug design may be discovered that will afford selective and specific MAPK modulation.

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