Cell Signalling Pathways

Cells communicate with each other, exchanging stimulatory and inhibitory signals (Fig. 9.4). These may be autocrine (affecting one cell), paracrine (between neighbouring cells) and endocrine (acting at a distance). Cell functions are modified by an enormous number of molecules, ranging from small and diffusible polypeptides to large protein complexes that act at the cell surface. Gap junctions between cells allow the passage of small molecules; cell-specific receptors are required for distant actions. These may lie on the cell membrane externally, within the cytoplasm or within the nucleus.

The largest group of cell membrane receptors function as protein tyrosine kinases which phosphorylate tyrosine residues on target proteins, altering their function. The prototype cell surface receptor has three 'domains': an external domain on the cell surface to which the agonist (ligand)

Figure 9.3. The process of translation - each of the 20 amino acids which form a protein have a specific genetic identity which is 'called up' by the triplet sequences of codons transcribed onto mRNA.

Autocrine

A cell produces and can respond to a growth factor through specific receptors

Autocrine

A cell produces and can respond to a growth factor through specific receptors

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o

One cell type produces a growth factor to which a different cell type located close by can respond through specific receptors

By circulation Endocrine

Paracrine

One cell type produces a growth factor to which a different cell type located close by can respond through specific receptors

By circulation Endocrine

Figure 9.4. Mechanisms of cell-to-cell communication by humeral mediators.

binds, a transmembrane domain and an internal domain, which on receiving the stimulus modulates intracellular enzymatic activity, either directly or via 'second messenger' systems (Fig. 9.5). A major class of cell-surface receptor exist whose transduction processes are linked to G-proteins (guanine-nucleotide-binding proteins), which translocate between the membrane and cytoplasm and can modulate a diversity of intracellular targets.

'Second messenger' systems activated by the signals transmitted across the cell membrane may induce cytoplasmic metabolic processes directly or act via transcription factors on nuclear DNA to activate gene expression and growth control. An example is stimulation of cell growth due to activation of the cytoplasmic enzyme serine/threonine protein kinase C (PKC) which is widely distributed in normal tissues and stimulates DNA synthesis. DNA-binding proteins acting as transcription factors may also be activated through cAMP-protein kinase, a second messenger system.

Specialized receptors for lipid-soluble hormones reside in the nucleus. When bound to their specific hormone they act

Cell signalling pathway

Active ligand Inactive

Active ligand Inactive

Figure 9.5. Cell signalling pathways.

as transcription factors, side-stepping cell-membrane receptors and cytoplasmic second messengers. These nuclear receptors are related by homologous sequences and form a 'superfamily' of hormone receptors.

Each of these signal transduction mechanisms have been shown to be dysregulated in cellular transformation and malignant progression.

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