Most signaling molecules are secreted by one cell and bind to receptors expressed by a target cell. Cell-cell signaling can occur by direct cell contact or by endocrine, paracrine, and autocrine signaling. The steroid hormones, thyroid hormone, vitamin D3, and retinoic acid are small hydrophobic molecules that cross the plasma membrane of their target cells and bind to intracellular transcription factors. Other small signaling molecules include nitric oxide, neurotransmitters, and plant hormones. The widest variety of signaling molecules in animals are peptides, ranging from only a few to more than 100 amino acids. This group of molecules includes the growth factors that regulate animal cell growth and development.
The largest family of cell surface receptors, including the receptors for many hormones and neurotransmitters, transmit signals to intracellular targets via the intermediary action of G proteins, which are regulated by GTP binding. Cyclic AMP is an important second messenger in the response of animal cells to a variety of hormones and odorants. Most actions of cAMP are mediated by protein kinase A, which phosphorylates both metabolic enzymes and the transcription factor CREB.
The receptors for most growth factors are tyrosine kinases. Other receptors act in association with nonreceptor tyrosine kinases, including members of the JAK family, which phosphorylate and activate STAT transcription factors, and members of the Src family, which function downstream of a variety of growth factor receptors as well as integrins and other cell adhesion molecules. The MAP kinase pathway is coupled to tyrosine kinase receptors by the small GTP-binding protein Ras, which initiates a protein kinase cascade leading to MAP kinase (ERK) activation. ERK then phosphorylates a variety of cytosolic and nuclear proteins, including transcription factors that mediate immediate early gene induction. Other MAP kinase pathways mediate responses of mammalian cells to inflammation and stress. Another major pathway downstream of tyrosine kinases is initiated by phosphorylation of the plasma membrane phospholipid PIP2 by PI 3-kinase. This leads to activation of the serine/threonine kinase Akt, which plays a key role in cell proliferation and survival. One of the targets of Akt is the protein kinase mTOR, which is a central regulator of cell growth and couples protein synthesis and autophagy to the availability of growth factors, nutrients, and cellular energy.
Members of the TGF-β receptor family are serine/threonine kinases that directly phosphorylate and activate Smad transcription factors. NF-κB transcription factors are activated in response to cytokines, growth factors, and a variety of other stimuli. Their activation is mediated by phosphorylation and degradation of inhibitory IκB subunits. The Wnt and Notch pathways play key roles in determination of cell fate during animal development. Wnt signaling acts by preventing degradation of β-catenin, which serves as a transcriptional activator. Notch signaling is mediated by direct cell-cell interactions, which induce proteolytic cleavage of Notch, followed by translocation of the Notch intracellular domain to the nucleus where it activates a transcription factor.
The activity of signaling pathways within the cell is regulated by feedback loops that control the extent and duration of signaling. Quantitative differences in activity can be critical to the biological outcome of signaling pathways. Different signaling pathways interact by crosstalk to regulate each other's activity. The extensive crosstalk between individual pathways leads to the formation of complex signaling networks. A full understanding of signaling within the cell will require the development of quantitative network models.