Page 88 - 85 cell signalling pathways

Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 88

Module 2: Figure JNK signalling

Interleukin-1

GPCR
RAC/
TRAF6 TAK1 Cdc42 G
12/13
P MEKK1
JIP1
P MKK7 PI3K-

P
P JNK
Cytochrome c
JNK
Caspases
Negative feedback
loop
APOPTOSIS P JNK ?
P

C-Jun ATF2 ELK1
JIP1

Proliferation,
embryonic development

The organization and topology of the c-Jun N-terminal kinase (JNK) pathway.
The c-Jun N-terminal kinase (JNK) pathway can be activated in many ways, including via different receptor mechanisms and by various environmental
stresses such as osmotic, redox and radiation stress. These different inputs are transduced by separate mechanisms that all feed into the JNK
signalling cascade. With regard to receptor activation, the JNK pathway can be activated by various cytokines such as interleukin-1 as illustrated
here. The interleukin-1 receptor (IL-1R) is composed of two receptor-binding domains that interact with interleukin-1 and a non-binding accessory
protein. Once activated by interleukin-1, the IL-1R recruits the adaptor protein tumour-necrosis-factor-receptor-associated factor 6 (TRAF6), which then
recruits the mitogen-activated protein kinase kinase kinase (MAPKKK) called transforming growth factor β-activated kinase 1 (TAK1) responsible for
initiating the phosphorylation cascade by phosphorylating MAPK/extracellular-signal-regulated kinase (ERK) kinase kinase 1 (MEKK1). The MEKK1
then phosphorylates the dual-specificity protein kinase MAPK kinase 7 (MKK7) responsible for phosphorylating the tyrosine and threonine residues on
JNK. This activation cascade occurs in the vicinity of the plasma membrane, where it is organized by the scaffolding protein JNK-interacting protein 1
(JIP1). Once JNK is phosphorylated, it leaves the multimolecular activation complex and then diffuses into the nucleus, where it activates transcription
factors responsible for controlling processes such as proliferation, apoptosis and embryonic development.

pathway, causes neurofibromatosis type 1-like syndrome ceptor for lipopolysaccharide (LPS) (Module 2: Figure Toll
(NFLS). receptor signalling).

Mitogen-activated protein kinase (MAPK)
signalling properties
p38 pathway
The different mitogen-activated protein kinase (MAPK)
The p38 pathway is one of the major signalling cassettes of
signalling pathways have a number of important properties
the mitogen-activated protein kinase (MAPK) signalling
that greatly enhance their signalling efficiency.
pathway. It functions in the control of apoptosis and the
release of cytokines by macrophages and neutrophils. The
pathway takes its name from the family of p38 kinases, Temporal aspects of mitogen-activated protein kinase
which are the MAPKs that interact with the final effectors (MAPK) signalling
(Module 2: Figure MAPK signalling). The outcome of these pathways is very dependent on tem-
The p38 pathway can be activated either by different poral aspects, particularly signal duration. For example,
receptor mechanisms or by various environmental stresses prolonged stimulation is necessary to induce cell prolifer-
such as osmotic, redox or radiation stress. For example, ation.
one of the targets of the p38 pathway that is activated
by UV irradiation is one of the Cdc25 enzymes that Fidelity
control cell cycle progression. Phosphorylation of Ser- Another important property is the fidelity of these sig-
323 on Cdc25B results in the binding of 14-3-3 protein, nalling pathways. The three major signalling pathways
which then prevents this enzyme from initiating entry into share many common features: they often share signalling
mitosis. components, they are often activated by similar inputs [es-
The Toll receptor signalling pathway provides an ex- pecially in the case of the c-Jun N-terminal kinase (JNK)
ample of how the p38 pathway is activated by a Toll re- and p38 pathways], and they can also regulate similar

C 2012 Portland Press Limited www.cellsignallingbiology.org