Cell Signaling

All cells receive and respond to signals from their environment. The binding of most extracellular signaling molecules to their receptor initiates a series of intracellular reactions that regulate virtually al aspect of cell behaviour, movement, proliferation and survival and differentiation.

5.1 General Principal of Cell Signaling

• Signals that pass between cells are far simpler than the sorts of massages that humans ordinarily exchange.
• In a typical communication between cells, the signaling cell produces a particular type of signal molecule that is detected by the target cell.
• The target cell possesses receptor proteins that recognize and respond specifically to the signal molecule.
• Example- To transmit a message from one person to another, information might first be written in ink on paper, then read aloud, then carried as electric impulses along a telephone wire, and finally expressed in the form of nerve impulses in the recipient’s brain.
• At successive steps along this communication pathway, different forms of signals are used to represent the same information; the critical points in transmission occur where the information is converted from one form to another. This process of conversion is called signal transduction.
• The receptor protein performs the first step in a series of transduction processes at the receiving end of the signaling pathway, in the target cell, where the incoming extracellular signal is converted to intracellular signals that direct cell behavior.

Figure 18- A simple intracellular signaling pathway activated by an extracellular signal molecule

Figure 19- The biding of extracellular signal molecules to either cell surface receptors or intracellular receptors

5.1 Modes of Cell-Cell Signaling Or Forms of Intracellular Signaling

There are four types of Cell-Cell Signaling.

1. Contact dependent
2. Paracrine
3. Synaptic
4. Endocrine

a) Contact Dependent or Direct Cell-Cell Signaling

Signaling by direct Cell-Cell (or cell-matrix) interactions plays a critical role in regulation the behaviour of cells in animal tissue. As name indicates the membrane bound signal molecules stablished the signals between the signalling cell and target cell.

b) Pararine Signaling

Paracrine signaling is a form of cell to cell communication in which a cell produces a signal (as local mediator like cytokine) to induce changes in nearby cells, altering the behaviour of those cells. Signaling molecules known as Paracrine factor diffuce over a relatively short distance.

c) Synaptic Signaling

It is similar to paracrine signaling but there is a special structure called the synapse between the cell originating and the cell receiving the signals. Synaptic signaling only occurs between cells with the synapse; for example between a neuron & the muscle that is controlled by neural activity and the signalling molecule is neurotransmitter.

d) Endocrine Signaling

The signaing molecules (hormones) are secreted by specialized endocrine cells and carried through the circulation to act on target cells at distant body sites.

5.2 Extracellular Signal Molecules and Their Receptors

There are five types of extracellular signal molecules, they are as follows

1. Steroid Hormone
2. Nitric Oxide & Carbon Monoxide
3. Neurotransmitter
4. Peptide Hormones & Growth Factors
5. Eicosanoids

a) Steroid Hormones & Their Receptors

The steroid hormones (including testosterone, estrogen, progesterone, corticosteroid) thyroid hormones, vitamin D3 are small hydrophobic molecules that diffuce across the plasma membrane of their target cells and bind to intracellular receptors.

Members of the nuclear receptor superfamily function as transcription factors and directly regulate gene expression in response to ligand binding.These receptors may function as activators or suppressors of their target genes.

b) Nitric Oxide (NO) & Carbon Monoxide (CO)

The simple gas NO and CO are important paracrine signaling molecules in the nervous system and other cell types.

NITRIC OXIDE- Arginine (amino acid)

Nitric Oxide Synthase

Nitric oxide

Crosses plasma membrane of target cell

Alter the activity of intracellular target enzymes.

CARBON MONOXIDE- Also functions as a signaling molecule in the nervous system and may act similarly as a neurotransmitter and mediator of blood vessel dilation.

c) Neurotransmitter

These are small hydrophilic molecules that carry signals between neurons or between neurons and other target cells at a synapse.

Example – Acetylcholine, Dopamine, Histamine etc.

d) Peptide Hormones & Growth Hormones

This group of molecules includes peptides hormones, neuropeptides and a diverse array of polypeptide growth factors. Cytokines regulates the development and differentiation of blood cells and control the activities of lymphocytes during the immune response.

Peptide hormones, neuropeptides and growth factors are unable to cross the plasma membrane of their target cells, so they act by binding to cell surface receptors.

e) Eicosanoids

The Eicosanoids are a class of lipids that function in paracrine and autocrine signaling. In contrast to the steroid hormones, they act by binding to cell surface receptors.

Example- Prostaglandins, prostacyclin, thromboxanes etc.

5.3 INTRACELLULAR SIGNALING PATHWAYS

Many cells surface receptors stimulates intracellular target enzymes, which may be either directly linked or indirectly coupled to receptors by G-protein.

In most cases, a chain of reactions transmit signals from the cell surface to a variety of intracellular targets, a process called Intracellular Signal Transduction.

The pathways are

1. The cAMP Pathway
2. The cGMP Pathway
3. Phospholipids & Ca²⁺
4. The PI 3-Kinase/Akt and m TOR pathways
5. MAP Kinase pathways
6. The JAK/STAT and TGF-β/Smad pathway
7. NF-KB signaling
8. The Hedgehog, Wnt & Notch pathway

a) The cAMP pathway : Second Messenger and Protein Phosphorylation

Another second messenger used in many different cell types is cyclic adenosine monophosphate (cyclic AMP or cAMP), a small molecule made from ATP. In response to signals, an enzyme called adenylyl cyclase converts ATP into cAMP, removing two phosphates and linking the remaining phosphate to the sugar in a ring shape.

Once generated, cAMP can activate an enzyme called protein kinase A (PKA), enabling it to phosphorylate its targets and pass along the signal. Protein kinase A is found in a variety of types of cells, and it has different target proteins in each. This allows the same cAMP second messenger to produce different responses in different contexts.

b) cGMP : Second Messenger

cGMP is also an important second messenger in animal cell. One of the major mechanism through which the effects of Nitric Oxide are mediated the production of the second messenger cyclic GMP (cGMP). Nitric Oxide can stimulate production of cGMP by interacting with the haem group of the enzyme souble guanylate cyclase (sGC). This interaction allows sGC to convert GTP into cGMP.

cGMP can also be converted back to GTP by proteins known as phosphodiesterases.

c) Phospholipids & Ca²⁺ : Second Messenger

Hydrolysis of phsphatidylinositol 4,5 bisphosphate (PIP₂) yield diacylglycerol and inositol 1,4,5-triphosphate (IP₃), which activate protein kinase C and mobilize Ca²⁺ from intracellular stores respectively. Increased level of cytosolic Ca²⁺ then activate a variety of target proteins, including Ca²⁺ / calmodulin dependent protein kinase.

Example- Myosin light chain kinase

CaM Kinase

Adenylyl cyclase

Phosphodiesterase

In electrically excitable cells of nerve and muscle, level of cytosolic Ca²⁺ are increased by the opening of voltage gated Ca²⁺ channels in the plasma membrane. It triggers the release of neurotransmitter in neurons and muscle contraction in the muscle cell.

d) The PI ₃ – kinase / Akt and MTOR Pathways

In addition to being cleavage into diacylglycerol and IP₃, PIP₂ can be phosphorylated to the distinct second messenger PIP₃ by the enzyme PI-3 Kinase. This leads to activation of the protein-serine / threonine kinase Akt. The target of Pkt include critical transcription factors like members of the foxo family, the protein kinase GSk-3 & the protein kinase MTOR.

e) MAP Kinase Pathway

The MAP kinase (for mitogen activated protein kinase). In animal cells the best characterized forms of MAP kinase are coupled to growth factor receptor by 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 protein.

f) The JAK / STAT and TGF-β / Smad Pathway

STAT proteins (for signals transducers and activators of transcription) are transcription factors that contain SH2 domains and are activated directly by the JAK protein- tyrosine kinases associated with cytokine receptor. Tyrosine phosphorylation promotes the dimerization of STAT proteins, which then translocate to the nucleus where they stimulate transcription of their target genes.

Members of the TGF-β receptor family are protein serine / threonine kinases that directly phosphorylates and activate Smad transcription factors.