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Cells respond to extracellular signals produced by other cells or by themselves. This mechanism, called cell signaling, allows cell-cell communication and is necessary for the functional regulation and integration of multicellular organisms. Our discussion in this chapter not only provides the basis for understanding normal cell function but serves also as an introduction to the role of abnormal cell signaling in human disease.

Signaling molecules are either secreted or expressed at the cell surface of one cell. Signaling molecules can bind to receptors on the surface of another cell or the same cell.

Different types of signaling molecules transmit information in multicellular organisms, and their mechanisms of action on their target cells can be diverse. Some signaling molecules can act on the cell surface after binding to cell surface receptors; others can cross the plasma membrane and bind to intracellular receptors in the cytoplasm and nucleus.

When a signaling molecule binds to its receptor, it initiates a cascade of intracellular reactions to regulate critical functions such as cell proliferation, differentiation, movement, metabolism, and behavior. Because of their critical role in the control of normal cell growth and differentiation, signaling molecules have acquired significant relevance in cancer research.

Cell signaling mechanisms

Five major types of cell-cell signaling are considered (Figure 3-1):

Box 3-A Paracrine cell signaling

The first member of the Hedgehog family was isolated in a Drosophila mutant with bristles in a naked area in the normal fly. The most widely found hedgehog homolog in vertebrates is sonic hedgehog (Shh). Shh participates in the development of the neural plate and neural tube (see Chapter 8, Nervous Tissue). Shh binds to a transmembrane protein encoded by the patched gene and suppresses transcription of genes encoding members of the Wnt and TGF-β families and inhibits cell growth. Mutation of the patched homolog in humans (PTC) causes the Gorlin’s syndrome (rib abnormalities, cyst of the jaw, and basal cell carcinoma, a form of skin cancer).

Mechanisms of action of cell signaling molecules

Cell signaling molecules exert their action after binding to receptors expressed by their target cells. Target cells, in turn, can determine either a negative or positive feedback action to regulate the release of the targeting hormone (Figure 3-2).

Cell receptors can be expressed on the cell surface of the target cells. Some receptors are intracellular proteins in the cytosol or the nucleus of target cells. Intracellular receptors require that the signaling molecules diffuse across the plasma membrane (Figure 3-3).

Steroid hormones (Box 3-B) belong to this class of signaling molecules. Steroid hormones are synthesized from cholesterol and include testosterone, estrogen, progesterone, and corticosteroids.

Testosterone, estrogen, and progesterone are sex steroids and are produced by the gonads. Corticosteroids are produced by the cortex of the adrenal gland and include two major classes: glucocorticoids, which stimulate the production of glucose, and mineralocorticoids, which act on the kidneys to regulate water and salt balance.

There are three cell signaling molecules that are structurally and functionally distinct from steroids but act on target cells by binding to intracellular receptors after entering the cell by diffusion across the plasma membrane. They include thyroid hormone (produced in the thyroid gland to regulate development and metabolism), vitamin D3 (regulates calcium metabolism and bone growth), and retinoids (synthesized from vitamin A to regulate development).

Steroid receptors are members of the steroid receptor superfamily. They act as transcription factors through their DNA binding domains, which have transcription activation or repression functions. Steroid hormones and related molecules can therefore regulate gene expression.

In the androgen insensitivity syndrome (also known as the testicular feminization syndrome [Tfm]), there is a mutation in the gene expressing the testosterone receptor such that the receptor cannot bind the hormone, and hence the cells do not respond to the hormone. Although genetically male, the individual develops the secondary sexual characteristics of a female. We discuss the androgen insensitivity syndrome in Chapter 21, Sperm Transport and Maturation.

Cell signaling molecules bind to cell surface receptors

A large variety of signaling molecules bind to cell surface receptors. Several groups are recognized

Pathways of intracellular signaling by cell surface receptors

When a cell-signaling molecule binds to a specific receptor, it activates a series of intracellular targets located downstream of the receptor. Several molecules associated with receptors have been identified:

Clinical significance: Tyrosine kinases, targets for therapeutic agents

There are two main classes of tyrosine kinases: (1) receptor tyrosine kinases are transmembrane proteins with a ligand-binding extracellular domain and a catalyic intracellular kinase domain (see Figure 3-5), and (2) nonreceptor tyrosine kinases found in the cytosol, nucleus, and inner side of the plasma membrane.

The transmembrane receptor kinase subfamily belongs to the PDGF family, which includes c-kit. The subfamily of nonreceptor tyrosine kinases includes the Src family, the Fujinami poultry sarcoma/feline sarcoma (Fps/Fes), and Fes-related (Fer) subfamily.

In the absence of a ligand, receptor tyrosine kinases are unphosphorylated and monomeric. The nonreceptor tyrosine kinase is maintained in an inactive state by cellular inhibitor proteins. Activation occurs when the inhibitors are dissociated or by recruitment to transmembrane receptors that trigger autophosphorylation. Tyrosine kinase activity terminates when tyrosine phosphatases hydrolyze tyrosyl phosphates and by induction of inhibitory molecules.

The activity of tyrosine kinases in cancer cells can be disrupted by a protein that determines unregulated autophosphorylation in the absence of a ligand, by disrupting au to regulation of the tyrosine kinase, or by overexpression of receptor tyrosine kinase and/or its ligand. Abnormal activation of tyrosine kinases can stimulate the proliferation and anticancer drug resistance of malignant cells.

Tyrosine kinase activity can be inhibited by imatinib mesylate, a molecule that binds to the adenosine triphosphate (ATP)–binding domain of the tyrosine kinase catalytic domain. Imatinib can induce hematologic remission in patients with chronic myeloid leukemia and in tumors caused by activated receptor tyrosine kinase PDGF receptor (chronic myelomonocytic leukemia) and c-kit (systemic mastocytosis and mast cell leukemias). Imatinib has been successfully used in the treatment of gastrointestinal solid tumors.

The cAMP pathway

The intracellular signaling pathway mediated by cAMP was discovered in 1958 by Earl Sutherland while studying the action of epinephrine, a hormone that breaks down glycogen into glucose before muscle contraction.

When epinephrine binds to its receptor, there is an increase in the intracellular concentration of cAMP. cAMP is formed from adenosine triphosphate (ATP) by the action of the enzyme adenylyl cyclase and degraded to adenosine monophosphate (AMP) by the enzyme cAMP phosphodiesterase. This mechanism led to the concept of a first messenger (epinephrine) mediating a cell-signaling effect by a second messenger, cAMP. The epinephrine receptor is linked to adenylyl cyclase by G protein, which stimulates cyclase activity upon epinephrine binding.

The intracellular signaling effects of cAMP (Figure 3-6) are mediated by the enzyme cAMP-dependent protein kinase (or protein kinase A). In its inactive form, protein kinase A is a tetramer composed of two regulatory subunits (to which cAMP binds) and two catalytic subunits. Binding of cAMP results in the dissociation of the catalytic subunits. Free catalytic subunits can phosphorylate serine residues on target proteins.

In the epinephrine-dependent regulation of glycogen metabolism, protein kinase A phosphorylates two enzymes:

Note that an elevation of cAMP results in two distinct events: the breakdown of glycogen and, at the same time, a blockage of further glycogen synthesis. Also note that the binding of epinephrine to a single receptor leads to a signal amplification mechanism during intracellular signaling mediated by many molecules of cAMP. cAMP signal amplification is further enhanced by the phosphorylation of many molecules of phosphorylase kinase and glycogen synthase by the catalytic subunits dissociated from protein kinase A. It is important to realize that protein phosphorylation can be rapidly reversed by protein phosphatases present in the cytosol and as transmembrane proteins. These protein phosphatases can terminate responses initiated by the activation of kinases by removing phosphorylated residues.

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