Untitled Quiz

Cell Signaling

• Cells receive and respond to signals from their environment.
• Bacteria and unicellular eukaryotes respond to environmental signals and signals from other cells.
• Multicellular organisms have sophisticated cell-cell communication to meet the needs of the entire organism.
• Signaling molecules are secreted or expressed on one cell surface to bind to receptors on another cell.
• Binding of signal molecules to receptors starts a chain of reactions affecting cell behavior.
• Many cancers arise from problems in signaling pathways that control normal cell proliferation.

Signaling Molecules and Their Receptors

• Signaling molecules range from simple gases to proteins.
• Some molecules carry signals over long distances, while some act locally.
• Some molecules cross the plasma membrane to bind to intracellular receptors, others bind to cell surface receptors.

Modes of Cell Signaling

• Direct cell-cell signaling: Direct interaction of a cell with its neighbor (e.g., via integrins and cadherins).
• Signaling by secreted molecules: Three categories based on the distance over which signals are transmitted.

Endocrine Signaling

• Signaling molecules (hormones) are secreted by specialized endocrine cells and carried through the circulatory system to distant target cells.
• Example: Estrogen.

Paracrine Signaling

• Molecules released by one cell act on neighboring target cells.
• Example: Neurotransmitters.

Autocrine Signaling

• Cells respond to signaling molecules they themselves produce.
• Example: T lymphocytes respond to antigens by making growth factors that drive their proliferation, amplifying the immune response.
• Abnormal autocrine signaling often contributes to cancer.

Receptors

• Receptors may be located on the cell surface or inside the cell.
• Intracellular receptors respond to small hydrophobic molecules that can diffuse across the plasma membrane.
  • Examples: steroid hormones, thyroid hormone, vitamin D3, and retinoic acid.
• Steroid hormones are synthesized from cholesterol.
  • Testosterone, estrogen, and progesterone are sex steroids produced by the gonads.

Corticosteroids

• Glucocorticoids from the adrenal gland stimulate glucose production.
• Mineralocorticoids from the adrenal gland act on the kidneys to regulate salt and water balance.
• Ecdysone is an insect hormone that triggers larval metamorphosis to adults.
• Brassinosteroids are plant steroid hormones that control processes, including cell growth and differentiation.
• Thyroid hormone is synthesized from tyrosine in the thyroid gland and is pivotal for development and metabolism.
• Vitamin D3 regulates calcium metabolism and bone growth.
• Retinoic acid and retinoids are synthesized from vitamin A and crucial for vertebrate development.
• Receptors for these molecules belong to the nuclear receptor superfamily—transcription factors with domains for ligand binding, DNA binding, and transcriptional activation.
• Steroid hormones directly regulate gene expression.
• Ligand binding affects receptor activity differently depending on the receptor.

Ligand Binding

• Glucocorticoid receptors are bound to Hsp90 chaperones in the absence of hormone.
• Glucocorticoid binding displaces Hsp90, leading to binding of regulatory DNA sequences.
• Hormone binding can alter the activity of some receptors, for example, thyroid hormone receptors bind with corepressor complexes to repress transcription in the absence of hormones. Hormone binding leads to activation of transcription.

Nitric Oxide (NO)

• NO is a gas, crossing the plasma membrane to alter enzyme activity.
• NO is a paracrine signaling molecule in nervous, immune, and circulatory systems.
• Actions are local due to instability (half-life of a few seconds).
• The main target of NO is guanylyl cyclase, which stimulates cyclic GMP (cGMP) synthesis—a second messenger.
• NO signals dilation of blood vessels. It diffuses to smooth muscle cells, stimulating cGMP production and inducing muscle relaxation and blood vessel dilation.
• Carbon monoxide (CO) is another signaling molecule in the nervous system. It acts similarly to NO, as a neurotransmitter and mediator of blood vessel dilation.

Neurotransmitters

• Neurotransmitters carry signals between neurons or from neurons to other cells.
• Released when an action potential arrives at the end of a neuron.
• Neurotransmitters diffuse across the synaptic cleft and bind to receptors on the target cell surface.
• Neurotransmitters (hydrophilic) can't cross plasma membranes and bind to cell surface receptors.
• The receptors are often ligand-gated ion channels, opening when neurotransmitters bind.
• Neurotransmitter receptors can also involve enzyme-coupled receptors or G proteins.

Peptide Signaling Molecules

• Peptide signaling molecules (peptide hormones, neuropeptides, and growth factors) can't cross plasma membranes, acting by binding to cell surface receptors.
• Abnormalities in growth factor signaling cause various diseases, including cancers.
• Peptide hormones include insulin, glucagon, and pituitary hormones (e.g., growth hormone, follicle-stimulating hormone, prolactin).
• Neuropeptides are secreted by neurons; enkephalins and endorphins act as neurotransmitters and analgesics similar to morphine effects.
• Nerve growth factor (NGF) is a member of the neurotrophin family, regulating neuron development and survival.
• Epidermal growth factor (EGF) stimulates cell proliferation and is a prototype for growth factors.
• Platelet-derived growth factor (PDGF) is stored in blood platelets, released during blood clotting, and stimulates fibroblast proliferation, contributing to tissue regrowth.
• Cytokines regulate blood cell development and lymphocyte activities in immune responses.
• Membrane-anchored growth factors remain with the plasma membrane and function in direct cell-cell interactions.

Plant Hormones

• Gibberellins: stem elongation.
• Auxins: cell elongation.
• Ethylene: fruit ripening.
• Cytokinins: cell division.
• Abscisic acid: onset of dormancy.

G Proteins and Cyclic AMP Signaling

• Most ligands for cell-cell signaling bind to target cell surface receptors.
• Intracellular signal transduction: Surface receptors regulate intracellular enzymes transmitting signals from the receptor to other intracellular targets.
• Targets of signaling pathways frequently include transcription factors.
• Ligand binding to receptors triggers a chain of intracellular reactions to reach the nucleus, altering gene expression.
• G protein-coupled receptors are the largest family of cell surface receptors transmitting signals via guanine nucleotide-binding proteins (G proteins).
• G proteins have three subunits (α, β, and γ).
• Receptors have seven membrane-spanning α helices.
• Ligand binding induces a conformational change in the receptor, activating a G protein on the inner face of the plasma membrane.
• The activated G protein dissociates, carrying the signal to an intracellular target.
• G proteins were discovered during studies of cyclic AMP (cAMP) a second messenger mediating hormone responses.
• The α subunit binds guanine, regulating G protein activity. In its inactive state, α is bound to GDP. Hormone binding triggers exchange of GTP for GDP; the α and βγ complex dissociate and interact with their targets.
• cAMP is formed from ATP by adenylyl cyclase and is degraded to AMP by cAMP phosphodiesterase.
• Effects of cAMP are mediated by cAMP-dependent protein kinase (protein kinase A). Inactive protein kinase A has two regulatory and two catalytic subunits. cAMP binding to regulatory subunits causes dissociation. The free catalytic subunits phosphorylate serine on target proteins.
• In glycogen metabolism, protein kinase A phosphorylates two enzymes:
  • Phosphorylase kinase is activated, further activating glycogen phosphorylase for glycogen breakdown.
  • Glycogen synthase is inactivated, blocking glycogen synthesis.
• Signal amplification: Binding of a hormone molecule activates many intracellular target enzymes.
• G_s stimulates adenylyl cyclase, catalyzing cAMP synthesis.
• Protein kinase A phosphorylates many molecules of phosphorylase kinase, which phosphorylates many molecules of glycogen phosphorylase.
• In many animal cells, increases in cAMP activate transcription of genes with regulatory sequences called cAMP response elements (CREs). The free catalytic subunit of protein kinase A goes to the nucleus and phosphorylates the transcription factor CREB (CRE-binding protein).
• Phosphorylation of CREB recruits coactivators, expressing cAMP-inducible genes, which play roles in cell behavior.
• Protein kinases don't function alone. Protein phosphatases reverse protein phosphorylation, ending receptor-initiated kinase responses.
• cAMP can directly regulate ion channels in some animal cells; odorant receptors are G protein-coupled, stimulating adenylyl cyclase, and leading to an increase in cAMP. cAMP opens Na+ channels to initiate a nerve impulse.

###Tyrosine Kinases and Signaling by MAP Kinase, PI 3-Kinase, and Phospholipase C/Calcium Pathways

• Other cell surface receptors are directly linked to intracellular enzymes, including a large family of tyrosine kinases.
• Receptor tyrosine kinases phosphorylate their substrates on tyrosine residues.
• Receptor tyrosine kinases have an N-terminal extracellular ligand-binding domain, a transmembrane α helix, and a cytosolic C-terminal domain for protein tyrosine kinase activity.
• Binding of ligands (growth factors) to extracellular domains activates cytosolic kinase domains, resulting in phosphorylation of both receptors and intracellular target proteins.
• The first step involves ligand-induced receptor dimerization.
• Autophosphorylation of receptors gives phosphotyrosine-binding sites for downstream signaling molecules.
• Downstream signaling molecules have SH2 domains that bind to specific phosphotyrosine-containing peptides of activated receptors.
• SH2 domains were first recognized in tyrosine kinases related to Src, the oncogenic protein of Rous sarcoma virus.
• Nonreceptor tyrosine kinases stimulate intracellular tyrosine kinases.
• Cytokine receptors share structure with receptor tyrosine kinases, but their cytosolic domains lack catalytic activity.
• Ligand binding induces receptor dimerization and cross-phosphorylation of associated nonreceptor tyrosine kinases, which activate the receptor.