Trends in Endocrinology & Metabolism
Volume 16, Issue 1, January–February 2005, Pages 26-33
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‘Ins and outs’ of seven-transmembrane receptor signalling to ERK

https://doi.org/10.1016/j.tem.2004.11.008Get rights and content

Extracellular-signal-regulated kinases 1 and 2 (ERK1/2) are important members of the mitogen-activated protein kinase (MAPK) family and have emerged as key effector targets of activation by seven-transmembrane-spanning (G-protein-coupled) receptors (7TMRs). Regulation of ERK by 7TMRs is highly complex and dependent on cell type. Numerous studies have linked specific G protein pathways to ERK activation, but recent evidence suggests that some 7TMR-linked ERK signalling pathways might not be exclusively mediated by G proteins. In addition, the emergence of an ‘inside-out’ model for receptor tyrosine kinase (RTK) ‘transactivation’ by 7TMRs has enhanced our understanding of the ERK signalling system and further underscores the complexity of mitogenic regulation by 7TMRs.

Section snippets

Going it alone: G-protein-mediated pathways to ERK activation

Seven transmembrane-spanning receptors are most commonly associated with signals emanating from the activation of G proteins. Many 7TMRs use the Gα and Gβγ subunits of the G protein to transduce signals to ERK (Figure 1). For example, Gαq/11 subunit-directed phosphorylation and activation of ERK involves a pathway that is sensitive to inhibitors of phospholipase C (PLC), protein kinase C (PKC) and/or intracellular Ca2+. Gαs signalling to ERK is often inhibited by antagonists of PKA, whereas Gi

Picking the right team: β-arrestins and other scaffolds

Protein–protein interactions are crucial to the functionality of the ERK signalling network [4], and the number of known protein binding partners for ERK pathway components is multiplying rapidly. These interactions have three key functions: first, they ‘round up’ the components of a signalling pathway into a highly specific multiprotein complex; second, they sequentially present substrates to enzymes in an ideal orientation to maximize efficiency in the pathway; and third, they target the

Subcontracting: employing RTKs

The discovery that ERK activation mediated by 7TMRs is often almost indistinguishable from that mediated by the EGFR led to the proposal that G-protein- and RTK-mediated signalling pathways might converge with respect to ERK activation [43]. Subsequent research has identified two models of RTK ‘transactivation’ by 7TMRs. The first model is independent of ligand and requires a physical association between RTKs with 7TMRs and/or downstream second messengers such as Ca2+ and Src. The second

Concluding remarks

Although the distal section of the signalling network that connects 7TMRs to ERK activation is relatively well understood (Raf→MEK→ERK), the upstream signals that lead to the point of convergence at Raf are extremely diverse and crosstalk between pathways is profuse. It is through this complexity that ERK signalling achieves the specificity that is prerequisite to its differential response to numerous and diverse upstream commands. Such complexity, however, also makes our task of understanding

Acknowledgements

Work in the authors' laboratories is funded by grants from the National Health and Medical Research Council (NHMRC) of Australia. Arthur Christopoulos and Patrick Sexton are Senior Research Fellows of the NHMRC.

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