Protein scaffolds in MAP kinase signalling

Abstract

The mitogen-activated protein kinase (MAPK) pathway allows cells to interpret external signals and respond in an appropriate way. Diverse cellular functions, ranging from differentiation and proliferation to migration and inflammation, are regulated by MAPK signalling. Therefore, cells have developed mechanisms by which this single pathway modulates numerous cellular responses from a wide range of activating factors. This specificity is achieved by several mechanisms, including temporal and spatial control of MAPK signalling components. Key to this control are protein scaffolds, which are multidomain proteins that interact with components of the MAPK cascade in order to assemble signalling complexes. Studies conducted on different scaffolds, in different biological systems, have shown that scaffolds exert substantial control over MAPK signalling, influencing the signal intensity, time course and, importantly, the cellular responses. Protein scaffolds, therefore, are integral elements to the modulation of the MAPK network in fundamental physiological processes.

Figure 1. Model of a molecular scaffold for the MEK/ERK pathway

Molecular scaffolds bind to several components of the MAPK cascade, assembling them in a multiprotein complex. The close proximity of the kinases facilitates propagation of the signal.

Figure 2. MAPK specificity

Diverse extracellular inputs stimulate the Ras/Raf/MEK/ERK cascade and each can elicit a distinct cellular outcome.

Figure 3. Spatial regulation of MEK/ERK signalling by protein scaffolds

Molecular scaffolds regulate the subcellular distribution of components of the MAPK pathway. Both IQGAP1 and KSR bind to Raf, MEK and ERK and are thought to localise the kinases to the plasma membrane, while MP-1 (through it interaction with p14) localises active MEK and ERK to endosomes. Following activation, ERK is free to phosphorylate cytosolic targets, or translocate to the nucleus and activate nuclear targets. KSR binds to ERK dimers and restricts them to cytosolic targets. Like MP-1, β-arrestins localise Raf, MEK and ERK to endosomes. However, once activated ERK is prevented from translocating to the nucleus and is restricted to cytosolic targets by an unknown mechanism. Sef restricts MEK and ERK to the Golgi and, like β-arrestin, prevents translocation of ERK to the nucleus, limiting it to cytosolic substrates. GPCR, G-protein coupled receptor; RTK, receptor tyrosine kinase.