Signal Transduction Pathway

Signal Transduction

Understand what is meant by signal transduction and its uses

Signal transduction is the transmission of molecular signals from the outside of the cell into the cell via cell-surface receptors.

A cascade of events or biochemical changes within the cell (enzymatic or intracellular messengers).

Modification of cell membrane potential initiated by the movement of ions or out of the cell.

Signal transduction can be used to develop pharmacological agents that can potentiate or diminish signaling. (Signals can become exaggerated in cancer cells, suppression reduces proliferation).

Describe the different type of receptors

Receptors are found in the cytoplasm (adrenal steroids), nucleus (thyroid), cell membrane (protein, catecholamines).

Ionotropic: transmembrane ion channels that open in response to the binding of a ligand (nicotinic acetylcholine receptor).

Metabotropic: uses signal transduction mechanisms (G proteins) to activate a series of events using secondary messenger chemicals (glutamate, muscarinic acetylcholine receptors).

Enzyme-Linked Receptors: Intrinsic enzymatic activity or associated with intracellular enzymes.

GPCRs: coupled to G proteins which modulate the activity of ion channels and enzymes.

Ligand-Gated: allows specific ions to flow freely in response to binding of a chemical messenger.

Intracellular Receptors: Activation of these receptors located within a cell results in gene transcription.

Discuss the different types of signal transduction pathways

G proteins

cAMP dependent

Gαs or Gαi subunit,is activated when the ligand binds to the receptor and dissociates from the other subunits. It travels to adenyl cylcase and activates it. Adenyl cyclase converts ATP to cAMP, which then activates protein kinase A. Protein kinase A adds phosphates to other enzymes, changing their conformation and modulating their activity.

The pathway is modulated by the enzymatic activity of cAMP-phosphodiesterase and inactivation of adenylyl cyclase.

IP3/DAG

Upon binding of signal molecule, the α subunit is activated with GTP and travels to phospholipase C and activates it. Phospholipase C uses phospholipids to make IP₃ and DAG.

IP3 is released into the cytosol and interacts with a receptor on the ER to open calcium channels. The release of Ca evokes a cellular response.

DAG stays in the membrane and activates protein kinase c. Protein kinase C phosphorylates cytosolic proteins, which can elicit a cellular response.

Soluble kinases

JAK-STAT

Signal transducer and activator of transcription, mediated by cytokine signals. It transmits information from extracellular chemical signals to the nucleus, resulting in DNA transcription and expression of genes.

Consists of a cell surface receptor, a Janus kinase (JAK) and two signal transducer and activator of transcription (STAT) proteins.

Ligands (cytokines) bind to cell surface receptors, activating associated JAKs, increasing their kinase activity. They then phosphorylate tyrosine residues on the receptor, creating binding sites for proteins with SH2 domains.

These proteins (STATs) are recruited and their tyrosines are also phosphorylated by JAKs, forming hetero- or homodimers. They then translocate to the cell nucleus where they induce transcription of target genes.

Enzymatic activity

Tyrosine Kinase

Signaling molecules (Insulin, growth factors) bind to tyrosine kinase receptor. Neighboring tyrosine kinase receptor (also now active) associates, forming a cross-linked dimer.

Tyrosine kinase activity is activated through cross-phosphorylation, resulting in a series of enzymatic reactions that carry the signal to the nucleus, affecting protein transcription.

Steroid hormones

Steroid hormones pass through the plasma membrane and bind to receptor proteins in the membrane, then bind to the hormone-receptor complex and travel to the nucleus. Alternatively, some migrate straight to the nucleus, bind to receptor proteins, and then to the hormone-receptor complex.

The hormone receptor complex binds to hormone response elements of the DNA, affecting transcription.

Understand the different types of signal transducing messengers

G proteins
Bind to a receptor, activate an alpha subunit that goes onto activate a target enzyme, which generates a second messenger.

Kinases

Bind to receptors, activating associated JAKs on the receptor, which are responsible for generating secondary messengers.

Enzymatic

Bind to enzymatic receptor, activating it, resulting in generation of a secondary messenger.

Differentiate between first and second messengers

First messengers are the ligands that bind to cell surface receptors, activating the intracellular membrane pathways as they are unable to pass through the membrane.

Secondary messengers are non-protein intracellular signaling molecules that are made as a result of activation by first messengers which then go and bring out the intracellular response.