Cell Signaling and Signal Transduction Mechanisms in Cell Biology

Signal transduction

The process by which cells receive external signals through receptor molecules and convert them into a cellular response.

Receptor

Molecules that receive external signals and initiate a cellular response.

Transduction

The process of converting a signal into another form, often involving stepwise regulation of intracellular signaling proteins.

Cellular response

The outcome of signal transduction, which can involve gene expression, membrane transport, metabolism, cell growth/death, etc.

Signal transduction cascade

Sequential biochemical events that transfer a signal through a series of reactions activating intermediate molecules to a final target.

Amplification in signaling cascades

The process by which signaling cascades produce multiple intracellular activated molecules for every one receptor that is bound.

Juxtacrine signaling

Cell-cell communication that requires direct contact between cells via surface proteins.

Endocrine signaling

Hormones secreted into the bloodstream at low concentrations (10^-12 - 10^-9 M) without cell-cell contact, requiring high affinity receptors.

Paracrine signaling

Secreted ligands that target nearby cells at relatively high local concentrations (10^-9 - 10^-6 M) with lower affinity receptors and rapid responses.

Synaptic signaling

A type of paracrine signaling that occurs at synapses between neurons and targets, characterized by very high local concentrations (10^-6 - 10^-3 M) and rapid response times.

Autocrine signaling

A form of signaling where the sender and target are the same cell, with response times similar to paracrine signaling.

First messengers

Secreted molecules that act as ligands for receptors, which can be large (e.g., proteins) or small (e.g., amino acids, lipids).

Intracellular receptors

Receptors located inside the cell that respond to hydrophobic ligands such as steroid hormones and thyroid hormones.

Integral membrane proteins

A type of receptor that spans the plasma membrane and interacts with external signals.

Hydrophobic ligands

Ligands that can diffuse through the plasma membrane and bind to intracellular receptors.

Lipid-soluble hormones

Hormones that can pass through the plasma membrane to bind intracellular receptors, leading to altered gene expression.

Response time for endocrine signaling

Minutes to hours, depending on the hormone and its receptor.

Response time for paracrine signaling

Seconds to minutes, characterized by rapid and transient responses.

Response time for synaptic signaling

Milliseconds, due to the short distance between neurons and targets.

Response time for autocrine signaling

Similar to paracrine signaling, typically rapid.

Homeostasis

The maintenance of stable internal conditions among tissues and organs, facilitated by signal transduction.

Intracellular receptor example

Hormonal nuclear receptor

HRE

Highly specific to given hormone/NR

Steroid nuclear receptors

Initiate the signaling processes activated by steroid hormones (e.g. estrogen, glucocorticoid, progesterone, androgen)

Gene expression changes

Results in changes in gene expression over hours to days

Nuclear receptor proteins

Certain steroid receptors that are transcription factors

Unique property of nuclear receptors

Direct interaction with DNA and control of gene expression

Nuclear receptors' role

Key to embryonic development, adult homeostasis, and metabolism

Receptor binding process

After receptors bind their steroid, the receptor binds to specific sites on DNA, associates with coactivators, and activates transcription

FDA approved drugs targeting nuclear receptors

Targets of 10-20% of FDA approved drugs

Heterodimer nuclear receptor example

Retinoid X receptor LXR-β and liver X receptor RXR-α bound to DNA response element

DBD-hinge-LBD

DNA binding domain; ligand binding domain

Estrogen receptor α

Over expressed in ~70% breast cancer

Tamoxifen

ER antagonist in breast tissue

Intracellular receptor example 2

Thyroid nuclear receptor

Thyroid hormone

A lipid-soluble hormone that diffuses through the plasma membrane

Dimerization of receptor

Thyroid hormone binds receptor and promotes dimerization of receptor

Coregulatory proteins

Recruitment of coregulatory proteins promotes DNA binding and specific recognition of thyroid response element (TRE)

Signaling outcome of thyroid hormone

To turn on or off transcription

Second type of receptor for first messenger ligands

Integral membrane proteins

Second messengers

Small, intracellular molecules that transmit and amplify the initial signal from extracellular 1st messenger binding to receptors

Examples of second messengers

Inorganic ions or organic products of enzyme-catalyzed reactions (e.g. Ca2+, cyclic AMP, cyclic GMP, inositol triphosphate, Diacylglycerol, Phosphatidylinositol 3,4,5-triphosphate)

Protein phosphorylation

Modification by phosphorylation controls protein-protein interactions and enzymatic activity

Phosphorylation

Modification by phosphorylation controls protein-protein interactions and enzymatic activity.

Protein Kinase

An enzyme that catalyzes the transfer of phosphate groups from ATP to proteins.

Phosphatase

An enzyme that removes phosphate groups from proteins, reversing the action of kinases.

Enzymatically inactive

A state of a protein where it does not catalyze reactions.

Enzymatically active

A state of a protein where it catalyzes reactions.

Downstream signaling

The process by which signals are transmitted within a cell after receptor activation.

GTP-binding regulatory proteins

Proteins that bind and hydrolyze GTP, functioning as molecular switches.

G proteins

Molecular switches that exist in OFF/ON states and interact with downstream signaling proteins.

GDP-bound form

The inactive conformation of a G-protein when bound to GDP.

GTP-bound form

The active conformation of a G-protein when bound to GTP.

Guanine nucleotide exchange factors (GEFs)

Proteins that catalyze the exchange of GDP for GTP on G-proteins.

GTPase-activating proteins (GAPs)

Proteins that facilitate GTP hydrolysis, turning off the G-protein signal.

Receptor Binding

The interaction between a ligand and its receptor, initiating a signaling cascade.

Spare receptors

Receptors that are not fully occupied by ligands but still contribute to signaling.

Termination of signaling

The process of stopping a signal, which can involve reducing ligand availability or receptor desensitization.

Rapid re-uptake

The mechanism by which neurotransmitters are quickly taken back into the presynaptic neuron.

Acetylcholine esterase

An enzyme that breaks down acetylcholine in the synaptic cleft.

Receptor desensitization

A decrease in receptor responsiveness to the same concentration of agonist.

Protein-protein interactions

Interactions between proteins that can be modulated by phosphorylation.

Amplification

The process by which a small signal is enhanced to produce a larger cellular response.