Regulation of IKK - Transcription Factors NF-kappaB - page 24

3 Regulation of IKK
Hans Häcker and Michael Karin

CONTENTS

3.1 Introduction .................................................................................................... 25

3.2 Background .................................................................................................... 26

3.3 The IKK Complex and Its Mechanism of Activation ................................... 26

3.4 Signaling Pathways Leading to IKK Activation............................................ 31

3.4.1 Activation of the NF- B Pathway by Members of the

TNF Receptor (TNFR) Family .......................................................... 32
3.4.1.1

κ

Activation of the Classic NF- B Pathway by

TNFR Family Members ..................................................... 32

κ

3.4.1.2 Activation of the Alternative NF- κ B Pathway................... 37

3.4.2 Activation of the NF- B Pathway by Members of the

IL-1R/TLR Family ............................................................................. 38

κ

3.4.3 Activation of the NF- B Pathway by T Cell and B Cell

Receptors ............................................................................................ 40

κ

B Pathway by DNA-Damage ....................... 43
3.5 Summary ........................................................................................................ 44
References................................................................................................................ 45

3.4.4 Activation of the NF- κ

3.1 INTRODUCTION

NF- B proteins are dimeric transcription factors whose activation is regulated by

protein phosphorylation. In their inactive state, NF-

κ

κ B dimers are sequestered in the

cytoplasm, bound to inhibitory I Bs). Cell stimulation leads to phos-

phorylation, ubiquitination, and degradation of I

κ B proteins (I κ

κ B proteins, which allows NF- κ B

to translocate to the nucleus and activate target genes. NF- κ B activity can be further

modulated through direct phosphorylation, although I κ B phosphorylation represents

the primary mode of regulation. Phosphorylation of I B proteins is accomplished

by several protein kinases, the most important of which are I

κ

κ B kinase α (IKK α )

and ΙκΒ kinase β (IKK β ), which together represent the major point of regulation of

the NF- B activation pathway. Although similar, gene knockout studies clearly

demonstrate that IKK

κ

are functionally nonredundant — perhaps due to
different substrate specificities. While IKK

α and IKK β

β is essential for NF- κ B activation by

proinflammatory factors, such as TNF α , IL-1, and LPS, IKK α is primarily involved

in NF- B activation in response to a subset of TNF-R family members, such as B

cell activating factor-receptor (BAFF-R), CD40, and the lymphotoxin

κ

β receptor

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