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14.3Intercellular Signal Transduction

Figure 14-1A is a schematic diagram of a signal transduction between cells. In the living body, cells (tissues and organs) interact to maintain homeostasis of the entire organism. The stimulus received by a cell not only affects that cell but also those that are further away. Substances involved in such intercellular signal transductions include hormones and growth factors (i.e., proliferative factors).

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14.3.1

Hormones

Hormones are chemical substances and signal molecules produced in specific organs that act at very low concentrations on distant organs by traveling through the blood stream. Hormones vary diversely in type and action (see Table 14-1 for reference). Signal transduction by hormones is based on the general mechanism of signal transduction, which begins from the recognition of a hormone by a receptor and eventually ends by causing changes in proteins and genes through intracellular signal transduction. Most hormones bind to G-protein-coupled receptors to initiate signal transduction involving G proteins. However, downstream signals often differ according to the type of hormone. The actions of hormones in a living organism and their significance have been discussed in Chapter 5.

Figure 14-7 Signal transduction by proteolysis

Caspase precursors form dimers upon receiving the apoptotic signal and mutually degrade themselves. Of the degradation products of the caspase precursor, two subunits bind again to become activated caspases. In this way, activation signals are transduced by proteolysis.

Table 14-1 Representative hormones and actions

*Represents a normal protein in the absence of mutation or abnormal expression (also see Column Selection 2 Chapter 15).

column

Apoptosis

Column Figure 14-2. Chromatin condensation due to apoptosis of HeLa cells

In this photo, only the cell nuclei have been stained. The pale oval ones are normal, whereas the one with dark particles gathering together is a cell nucleus currently undergoing apoptosis. Apoptosis was artificially induced in the HeLa cells shown here. HeLa cell is a human derived cell type used for research purposes.

When observing the growth of nematodes, you will find that certain cells seem to be destined to die during growth (see Selection 2 Chapter 19, Column Figure 19-1). Such cell death is called programmed cell death or apoptosis. Apoptosis is a normal process and can be observed throughout the life of a mature organism. One familiar example of apoptosis is the loss of a tadpole’s tail.

In addition to the development and growth process of living organisms, apoptosis is an indispensable part of homeostasis as well as important to the establishment of the immune and nervous systems (see Chapter 21). Morphologically, apoptosis is characterized by a series of structural changes such as the loss of the nuclear membrane, chromatin condensation in the nucleus, and intracellular vesicle formation, which eventually leads to cell shrinkage and death (Column Figure 14-2).

One important component of the apoptosis pathway is the proteolytic enzyme called caspase as described earlier. The functions of activated caspases include the destruction of organelles, intracellular signal transduction pathways, and DNA repair and replication mechanisms.

Activation of caspases is induced by extracellular signals through the activation of the Fas protein. Other pathways of caspase activation include the release of cytochrome c, an enzyme found in the mitochondria, caused by cellular damage or other reasons, and activation of signal transduction pathways for inactivating caspase inhibitor proteins (the latter is not shown in Column Figure 14-3).

Signal transduction pathways activated by growth factors or cell adhesion inhibit various signal transduction pathways related to apoptosis. The cancellation of such inhibitions will also initiate apoptosis. In cells that have evaded apoptosis through such inhibition mechanisms, the lack of growth factors or cell exfoliation results in apoptosis. For instance, the survival of both endothelial and epithelial cells is highly dependent on mutual adhesion and adhesion with the extracellular matrix. Cells lacking such adhesion are eliminated from tissues through apoptosis. This mechanism protects living organisms from abnormal cell proliferation as well as prevents isolated cells from adhering to and multiplying in inappropriate regions

Column Fig. 14.3 Apoptosis signals leading to cell death

Although the process of caspase activation is not included in this figure, several pathways are known to activate caspases.

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14.3.2

Cell growth factors

Growth factors are essentially signal molecules that generate signals to promote cell growth and proliferation. As an increasing number of growth factors that were considered to be principally involved in cell growth when they were first discovered are found to have other functions besides promoting growth and proliferation, soluble glycoproteins released from cells, including growth factors, are being collectively referred to as cytokines*3 (see Chapter 21).

*3 The concept of cytokines focuses not on the results but on the process of growth factor actions, considering that the mechanisms of cytokines, including growth factors, initiate signal transduction as first messengers.

Growth factors were discovered through the search for factors required for continuously culturing dissociated cells obtained from living organisms. Their greatest feature was thus thought to be their mitogenic action. In the living organism, growth factors usually have autocrine or paracrine actions, most of which are local actions but last for a long time compared to that of hormones (from several hours to several days). Table 14-2 shows examples.

Table 14-2 Examples of growth factors

A-kinase is inactive as a heterotetramer. However, when cAMP binds to the regulatory subunit, the catalytic subunit dissociates, allowing A-kinase to demonstrate catalytic activity. When cAMP dissociates, A-kinase becomes a tetramer again and hence inactivated.

Here, the signal transduction pathway of a growth factor called platelet-derived growth factor (PDGF) is discussed as an example. Firstly, PDGF binds to a PDGF receptor on the cell membrane as the first messenger. The kinase activity of the PDGF-binding receptor is activated, and it then activates various signal transduction molecules such as phospholipase C. These signals then activate genes involved in cell proliferation, such as c-myc, within several minutes to 1 or 2 hours. Chapter 15 will describe the close relationship between the activation of signal transduction pathways by growth factors and cell proliferation or cancer.

While this chapter focuses on the main components used for signal transduction, Chapter 15 will discuss receptors, which serve as the gates to cells in signal transduction pathways.

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