Modes of Cell-Cell Signaling: Most signaling molecules are secreted by one cell and bind to receptors expressed by a target cell. Cell-cell signaling is divided into three general categories (endocrine, paracrine, and autocrine signaling) based on the distance over which signals are transmitted.
Steroid Hormones and the Nuclear Receptor Superfamily: The steroid hormones, thyroid hormone, vitamin D3, and retinoic acid are small hydrophobic molecules that diffuse across the plasma membrane of their target cells and bind to intracellular receptors. Members of the nuclear receptor superfamily function as transcription factors to directly regulate gene expression in response to ligand binding.
Nitric Oxide and Carbon Monoxide: The simple gases nitric oxide and carbon monoxide are important paracrine signaling molecules in the nervous system and other cell types.
Neurotransmitters: Neurotransmitters are small hydrophilic molecules that carry signals between neurons or between neurons and other target cells at a synapse. Many neurotransmitters bind to ligand-gated ion channels.
Peptide Hormones and Growth Factors: 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 peptide hormones, neuropeptides, and growth factors.
Eicosanoids: The eicosanoids are a class of lipids that function in paracrine and autocrine signaling.
Plant Hormones: Small molecules known as plant hormones regulate plant growth and development.
G Protein-Coupled Receptors: 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.
Receptor Protein-Tyrosine Kinases: The receptors for most growth factors are protein-tyrosine kinases.
Cytokine Receptors and Nonreceptor Protein-Tyrosine Kinases: The receptors for many cytokines act in association with nonreceptor protein-tyrosine kinases.
Receptors Linked to Other Enzymatic Activities: Other kinds of cell surface receptors include protein-tyrosine phosphatases, protein-serine/threonine kinases, and guanylyl cyclases.
The cAMP Pathway: Second Messengers and Protein Phosphorylation: 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.
Cyclic GMP: Cyclic GMP is also an important second messenger in animal cells. Its best-characterized role is in visual reception in the vertebrate eye.
Phospholipids and Ca2+: Phospholipids and Ca2+ are common second messengers activated downstream of both G protein-coupled receptors and protein-tyrosine kinases. Hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) yields diacylglycerol and inositol 1,4,5-trisphosphate (IP3), which activate protein kinase C and mobilize Ca2+ from intracellular stores, respectively. Increased levels of cytosolic Ca2+ then activate a variety of target proteins, including Ca2+/calmodulin-dependent protein kinases. In electrically excitable cells of nerve and muscle, levels of cytosolic Ca2+ are increased by the opening of voltage-gated Ca2+ channels in the plasma membrane and ryanodine receptors in the endoplasmic and sarcoplasmic reticula.
The PI 3-kinase/Akt and mTOR Pathways: In addition to being cleaved into diacylglycerol and IP3, PIP2 can be phosphorylated to the distinct second messenger PIP3. This leads to activation of the protein-serine/threonine kinase Akt, which plays a key role in cell survival. One of the targets of Akt signaling is the protein kinase mTOR, which is a central regulator of cell growth and couples protein synthesis to the availability of growth factors, nutrients, and cellular energy.
MAP Kinase Pathways: The MAP kinase pathways are conserved chains of protein kinases activated downstream of a variety of extracellular signals. In animal cells, the best-characterized forms of MAP kinase are coupled to growth factor 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. Components of MAP kinase pathways are organized by scaffold proteins, which play an important role in maintaining the specificity of MAP kinase signaling.
The JAK/STAT and TGF-β/Smad Pathways: STAT proteins are transcription factors that contain SH2 domains and are activated directly by the JAK protein-tyrosine kinases associated with cytokine receptors. Members of the TGF-βreceptor family are protein-serine/threonine kinases that directly phosphorylate and activate Smad transcription factors.
NF-κB Signaling: Members of the NF-κB family of 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 Hedgehog, Wnt, and Notch Pathways: The Hedgehog, Wnt, and Notch pathways play key roles in determination of cell fate and patterning during animal development. The Hedgehog and Wnt signaling pathways both act by preventing degradation of transcription factors in complexes in the cytoplasm. 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 interacts with a transcription factor to affect expression of target genes.
Integrins and Signal Transduction: Binding of integrins to the extracellular matrix stimulates the FAK and Src nonreceptor protein-tyrosine kinases, leading to activation of phospholipase C, PI 3-kinase, and Ras/Raf/ERK signaling pathways.
Regulation of the Actin Cytoskeleton: Signaling from integrins as well as growth factor receptors induces alterations in cell movement and cell shape by remodeling the actin cytoskeleton. These cytoskeletal alterations are mediated by members of the Rho subfamily of small GTP-binding proteins.
Feedback and Crosstalk: The activity of signaling pathways within the cell is regulated by feedback loops that control the extent and duration of signaling. Different signaling pathways also interact to regulate each other’s activity.
Networks of Cellular Signal Transduction: 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.
