PArrestinbinding and MAP kinase activation

The P-arrestins appear to play a dual role in GPCR signalling. They serve both to terminate G protein-dependent signals by hampering receptor-G protein coupling, and to induce novel signalling properties of the receptor by acting as adapters or scaffolds for signalling proteins that make up part of the ERK/mitogen-activated protein kinase (MAP kinase) signalling pathway.

MAP kinases are a family of evolutionarily conserved serine/threonine kinases that are involved in the transduction of externally derived signals regulating cell growth, division, differentiation and apoptosis. ERK1 and ERK2 were the initial MAP kinases to be discovered. They are important for the control of the G0-G1 cell cycle transition and the passage of cells through mitosis or meiosis. They perform the last step in a specific phosphorylation cascade in the cytosol, with the following sequence (Figure 132):

• Inactive Raf (a 74 kDa serine/threonine kinase) is in a complex with '14-3-3' proteins and, when activated, it will phosphorylate two serine residues on MEK.

• Phosphorylated MEK is active and will phosphorylate the tyrosine and threonine residues on ERK.

• Once phosphorylated/activated, ERK will phosphorylate a variety of membrane, cytoplasmic and cytoskeletal substrates as well as nuclear transcription factors involved in DNA synthesis and cell division. This last process implies the relocation of active ERK to the nucleus.

What keeps the signal on track appears to be the assembly of the cascade components onto the scaffold composed of '14-3-3' and MP1.

Several other kinase pathways follow the same pattern in mammalian cells (Figure 133). Each cascade consists of three protein kinases: a terminal MAP kinase

Figure 132 Stimulated growth factor receptors initiate signal transduction via the MAP kinase pathway. Reprinted from Geoffrey M.Cooper, The Cell: A Molecular Approach, 4th edn., © (2007), with permission from ASM Press, Washington DC.

and two upstream kinases (analogous to Raf and MEK) that regulate its activity. Additional MAP kinases are JNKs/SAPK and p38/HOG1. They are involved in regulation of growth arrest, apoptosis and activation of immune cells in response to stresses. In many cases, binding of the component kinases to a scaffolding protein controls

Stimulus

Upstream kinases

Stimulus

Growth

Cytokines

factors

Cellular stress

MEKKs

kinases

Raf f MEK

MEKKs

MEK MKKs

ERK JNK/p38 transcription factors

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