What is Cell Signaling?

It allows cells to perform various cellular activities, coordinate, and interact with other cells. All cells of an organism receive signals from their environments and respond accordingly. Even the unicellular eukaryotes receive signals secreted by other cells and respond. In the case of yeast, mating takes place by signaling between the yeast cells. Communication by cell signaling in a multicellular organism has become a vast and important part of various fields of biology.

Cell signaling is carefully regulated in plants and animals by a large variety of signaling molecules generated or expressed on the surface of a cell and bind to the receptors expressed by other cells. As the signaling molecule binds to its receptor, a series of reactions and changes regulate cellular activities like differentiation, metabolism, proliferation, and movements.

Basic Steps of Cell Signaling 

Receive → Transduce → Respond to signal

Signal/Inputs

A signaling molecule associates or binds with a receptor and initiates cell signaling. It is also known as a ligand. The signaling molecules can be proteins, light, smell, taste, nutrients, pressure, pH, temperature, hormones, oxygen, sound, and morphogens.

Signals are categorized into three groups based on where they work:

1. Autocrine - Same cell (for example, cytokine IL-1 (interleukin-1) in monocytes and insulin)
2. Paracrine - Nearby cells (for example, growth factor and clotting factor)
3. Endocrine - Distant cell (for example, progesterone and testosterone)

Component of Signaling

Receptors

They are present either inside the cytoplasm or on the surface of the membrane. Receptors present inside the cytoplasm are cytoplasmic proteins and ligands. The signals for such receptors are usually steroid hormones or lipid molecules. However, receptors present over the surface are membrane proteins that serve as receptors to most signaling molecules.

The three categories of receptors are as follows:

1. G-protein coupled receptors (GPCRs)

GPCRs are seven transmembrane helices. G-proteins are heterotrimeric proteins made up of three subunits (alpha, beta, and gamma). The human genome encodes more than 1000 GPCRs. GPCRs transduce a wide variety of information such as light, smell, taste, and hormones. About 30% of current drug targets are GPCRs. Glucagon-adrenaline signaling is an example of GPCR where the GPCR acts as a receptor while glucagon-adrenaline acts as a ligand.

In the above diagram of the glucagon-adrenaline signaling pathway, as glucagon-adrenaline binds to the GPCR, its conformation changes. The alpha-subunit of the G-protein has activated, which in turn activates adenylate cyclase. The adenylate cyclase, along with the alpha-subunit attached to GTP (guanosine triphosphate), catalyzes the conversion of ATP (adenosine triphosphate) into many cAMP (cyclic adenosine monophosphate) molecules. Now, the increased amount of cAMP activates the enzyme protein kinase A (PKA) that strengthens the response of the signal molecules. Eventually, glucose-1-phosphate molecules are produced in response.

2. Receptor tyrosine kinases (RTKs)

RTKs belong to the sub-class of tyrosine kinase. The human genome encodes about 60 RTKs, and many of these are associated with cancer progression. In addition, EGF (epidermal growth factor) signaling pathway uses RTKs.

Steps involved in the EGF signaling pathway:

1. EGF causes extracellular epidermal growth factor receptors (EGFRs) to dimerize.
2. The intracellular kinase domain becomes active, and it "transphosphorylates".
3. The signal is amplified through a cascade of steps (the enzyme is turned "on" by the phosphorylation).
4. Ultimately, the terminal protein enters the nucleus and acts as a transcription factor, promoting gene expression.
5. Cellular activities such as survival, growth, and metabolism are altered in the response.

3. Ion channels 

These play an important role in the nerve impulse transmission across synapses for establishing the ion gradients across the cell membrane. The ion channels use receptors for signaling. These receptors have alpha-helices which detect the signal molecules and correspondingly change the conformation of the receptor. As the ion channel structure is changed, membrane depolarization takes place that moves the voltage-sensitive alpha-helices, resulting in the opening of the Na⁺-gated channels. As Na⁺-gated channels open, the membrane polarity changes. Afterward, these channels close, preventing the influx of Na⁺ and a simultaneous movement of K⁺ outside the cell. The membrane's repolarization occurs, and the voltage-sensitive alpha-helices present in the ion channels are returned to their original position. The process repeats itself, transmitting nerve impulses throughout the body. 

Response/Outputs

Every signal that binds to a receptor gives some output or response. These responses are categorized into two categories based on the effectiveness of the response in an organism.

These two categories of response or output are as follows:

1. The short-term response includes movement, endocytosis, and post-translational modification.
2. The long-term response includes gene expression, apoptosis, growth, and development.

Process of Signal Transduction

Extracellular signal interacts with the receptors in the plasma membrane and cause a first response that triggers a sequence of events.

1. Cascade of signal transduction
   • Sensory molecules (receptors) detect the signal.
   • Receptors activate the downstream molecules.
   • Down-stream molecules turn protein function gene expression on/off.
2. Amplification of signal transduction

Initial receptor molecules activate downstream molecules that further activate multiple components of these downstream molecules.

3. Feedback of signal transduction

• Positive feedback activates the downstream pathway.
• Negative feedback suppresses the downstream pathway.

Diseases

The defects in the genes associated with cell signaling cause a variety of severe diseases.

• Mutation in the CFTR (cystic fibrosis transmembrane conductance regulator) gene responsible for encoding proteins that conduct chloride ions across the epithelial cell causes cystic fibrosis.
• In cancer, the signaling pathway is constantly activated and allows cells to grow and divide continuously. The uncontrolled growth occurs due to a change or mutation in any downstream component that maintains the signaling pathway in the active state.

Important Aspects of Cell Signaling

Phosphorylation

It is a biological process in which a phosphate group associates with a biomolecule covalently. In cell signaling, phosphorylation is a very important process and play a crucial role in activating various enzyme. However, sometimes phosphorylation also causes inhibition of the cell signaling pathway. For example, when GPCR phosphorylates, the arrestin proteins bind to the phosphorylated GPCR, leading to the inflammation of the membrane. Phosphorylation has a great impact on transducing signals from the cell membrane to the nucleus. In the cell signaling pathway, phosphorylation takes place either at tyrosine kinase or serine/threonine kinase. Kinase is an enzyme that catalyzes phosphorylation and mediates cellular signal transduction. Overexpression or mutation, or any malfunction in kinase, can cause various diseases. Gleevac is considered a good inhibitor of kinase and is used to treat kinase-associated diseases. The phosphorylation process during cell signaling can be monitored by various experimental approaches such as western blotting, radioactivity, mass-spectrometry, and 2D-gel electrophoresis. Since kinase phosphorylates the protein molecules involved in the signaling pathway and phosphatase dephosphorylates these molecules, phosphorylation is considered a reversible process.

G-proteins

G-protein is a family of proteins that are also known as guanine-nucleotide binding proteins. It acts as a molecular switch and exists in two states inside the cells. It also transmits a wide variety of signals coming from the environment. For example, the G-protein present in the inner membrane of cells plays a central role in several signaling pathways. It naturally exists in a GDP (guanosine diphosphate) bound form but receives the signal and changes its conformation as a receptor. The GDP bound G-protein converts into GTP bound G-protein by guanidine exchange factor (GEF). GEF can be any protein that causes the switching of the GDP-bound form to the GTP-bound form. Since this molecular switch is reversible, GTP bounded protein further hydrolyzes into GDP bound G-protein by the enzyme GTPase (guanosine triphosphatase). All G-proteins carry out the hydrolysis of GTP to GDP and are active in their GTP-bound form.

Signaling monitoring

Signaling is a biological process that causes the cells to perform various activities by transducing signals into the nucleus over the genomic DNA (deoxyribonucleic acid). These signals act on the DNA and promote gene expression, responsible for various cellular activities such as growth, development, transcription. Thus, signaling can change gene expression or alter transcription factors or change the activity, specificity, and stability. It can be monitored through the following experimental approaches:

• RNA (ribonucleic acid) sequencing
• Quantitative reverse transcriptase/polymerase chain reaction (qRT/PCR)
• Microarrays
• Northern blot

Context and Applications

This topic is significant in many Life Sciences examination for both undergraduate and graduate courses, especially for

• Bachelors of Science in Zoology
• Bachelors of Science in Botany
• Bachelors of Science in Biotechnology
• Bachelors of Science in Biochemistry
• Bachelors of Science in Microbiology
• Master of Science in Biochemistry
• Master of Science in Biotechnology
• Master of Science in Microbiology
• Master of Science in Microbial Biotechnology

Related Concepts

1. Cell communication
2. Desmosomes
3. Intercellular bridges
4. Gap junctions