14.1: Introduction to Signal Transduction

There are three primary modes of intercellular communication. These are

1. direct contact between signaling molecules bound to the membranes of two adjacent cells,
2. short-range soluble signals that diffuse over short distances, and
3. long-range soluble signals that are secreted into the circulation to be carried anywhere in the body.

An example of juxtacrine signaling is exemplified by the activity of some cell adhesion or ECM proteins, such as laminin, that do not just allow a cell to move over them, but act as signals to promote increased motility. This likely happens by activation of integrin receptors on the moving cell, which then initiate and coordinate changes through the rest of the cell to accomplish the change in activity. Another example is the Delta-Notch pathway used in embryonic patterning.

Figure \(\PageIndex{1}\). Delta-Notch signaling.

Delta, a transmembrane protein on the signaling cell, binds to Notch, a receptor on the receiving cell. Notch alters its conformation, allowing its cytoplasmic domain to be cut off by g-secretase. The cytoplasmic domain then translocates into the nucleus, where it acts as an activating transcription factor by binding with CSL. In the example sketched in Figure \(\PageIndex{1}\)B, stochastic upregulation of delta in one cell activates notch in the surrounding cells, which then activates a specific differentiation pathway for them. Thus the central cell may be a sensory neuron, like a hair cell, while those immediately surrounding it are support cells like glia. This type of signaling imposes a spacing pattern on the expression of neurons (or other cell).

The Delta-Notch pathway is well characterized and somewhat more complicated than portrayed in the paragraph above. The cleavage of Notch involves two proteases and two sites. Once the Notch cytoplasmic domain binds to CSL, it displaces a number of co-repressors bound to the CSL, and also recruits MAM (Mastermind-1) as a coactivator. MAM recruits histone acetylases to allow further increase transcription of targeted genes, but also recruits kinases that initiate the process of targeting the Notch cytoplasmic domain for ubiquitin-mediated destruction. The expression of Notch-controlled genes is thus self-regulated and shuts off soon after Delta is no longer available. Reviewed in R.A. Kovall, Curr. Opin. Struct. Biol. 17: 117-27, 2007.

Diffusion limited signals from near neighbors is called paracrine signaling, and some- times the signals can act on receptors right on the cell that secreted the signal, which would be autocrine signaling. Paracrine signals are only active if they can bind to a cell above a critical concentration to activate a signaling pathway. Therefore, as the signals diffuse away from the source, there is a cutoff, beyond which the concentration of signal is insufficient to activate a receiving cell. Growth factors are often paracrine signals. Although they do often encourage growth, they are also often survival factors. In that context, Nerve Growth Factor (NGF) is secreted by target cells that then reward the neurons that make the right connections by providing NGF for their survival. Those neurons that head off in the wrong direction, are unable to obtain NGF, and they do not survive, promoting efficiency and a better signal:noise ratio within the nervous system.

Endocrine signaling is essentially whole-body signaling. A signal produced by a hormone-producing gland is secreted into the bloodstream, where it becomes accessible to nearly any cell in the body. Of course, not every cell will respond to the hormone: like every other case of intercellular signaling, response is wholly dependent on receptors, so only the cells that have receptors to recognize the signal will react. For example, estrogen is released into the circulation, but in females, only some organs show significant impact when estrogen levels are significantly altered. Most tissues are unaffected. Endocrine signals may circulate in other extracellular fluids such as lymph.