Seminario 8 Señalización intercelular en organismos pluricelulares y diferenciación - Tomas Falzone

Cell Signaling in Multicellular Organisms

Introduction to Cell Signaling

• The seminar discusses cell signaling in multicellular organisms and its role in cellular differentiation.

• A signaling molecule is recognized by a receptor, typically a protein, initiating an intracellular signaling cascade that leads to various cellular responses.

Types of Cell Signaling

Substacrine Signaling

• Substacrine signaling occurs between adjacent cells where one cell has a signal anchored on its membrane and the other has the corresponding receptor.

• This type of communication requires direct contact between proteins on neighboring cells.

Communication with Extracellular Matrix

• Cells can also communicate with the extracellular matrix rather than directly with other cells, still classified as substacrine communication.

Autocrine and Paracrine Signaling

• Autocrine signaling involves a cell producing a signal that it can also receive, affecting itself or similar cells nearby.

• Paracrine signaling refers to signals released into the environment that affect nearby but different types of cells without direct contact.

Endocrine Signaling

• Endocrine signaling involves signals released into the bloodstream or lymphatic system, allowing them to reach distant target cells. This is crucial for long-range communication within the body.

Neurotransmission

• Neurotransmission is a specialized form of signaling where neurotransmitters are released from neurons to communicate with target muscle or nerve cells over significant distances through synaptic connections.

Characteristics of Signals

Soluble vs Non-Soluble Signals

• Signals can be categorized as soluble (e.g., hormones) which require dissolution in fluids for distribution, or non-soluble (e.g., certain ligands) which do not diffuse freely through mediums like blood or extracellular fluid.

Hydrophilic vs Hydrophobic Signals

• Hydrophilic signals are generally larger and charged, preventing them from crossing lipid membranes; they interact with receptors on the cell surface instead. Examples include peptide hormones and growth factors.

Signal Transduction Mechanisms

Lipid-Origin Signals and Receptor Locations

• Signals with a lipid origin can cross the plasma membrane, with receptors typically located in the cytoplasm or nucleus. This sets the stage for subsequent signaling mechanisms that will be explored.

Types of Receptors in Signal Transduction

• The discussion shifts to characterizing signaling based on signal molecules and their corresponding receptors, focusing on soluble, hydrophilic signals that interact with membrane-bound receptors.

Ion Channel Receptors

• Ion channel receptors are ligand-regulated structures that open upon ligand binding, allowing ion passage through the plasma membrane. These channels transition from a closed to an open state when activated by a signal.

• Examples include voltage-gated channels that respond to changes in membrane potential and ligand-gated channels activated by neurotransmitters like acetylcholine, facilitating ion flow crucial for neuronal communication.

G Protein-Coupled Receptors (GPCRs)

• GPCRs consist of seven transmembrane segments; upon activation by a signal (e.g., protein), they associate intracellularly with G proteins to activate enzymes such as adenylate cyclase, leading to intracellular signaling cascades via phosphorylation processes.

• The activation of adenylate cyclase converts ATP into cyclic AMP (cAMP), which acts as a secondary messenger activating various kinases like PKA, influencing gene transcription and cellular responses.

Tyrosine Kinase Receptors

• Tyrosine kinase receptors function as dimers; ligand binding induces dimerization and reciprocal phosphorylation between receptor units, initiating downstream signaling cascades involving SH2 domain-containing proteins that further propagate the signal within the cell.

• This auto-phosphorylation mechanism is critical for activating pathways related to cell growth and differentiation through kinase cascades affecting cytoskeletal remodeling and gene expression regulation.

Summary of Signaling Pathways

Cell Signaling Mechanisms

Role of Insulin in Glucose Regulation

• The example discusses the role of etiocina kinase in skeletal muscle, highlighting its effect on glucose incorporation and subsequent insulin release from pancreatic cells.

• Insulin is secreted into circulation via an endocrine signaling pathway, activating etiocina kinase receptors in distant target cells.

• Receptor activation leads to autophosphorylation, triggering a phosphorylation cascade that regulates gene expression related to glucose transporters.

Hydrophobic Signals and Their Mechanism

• Hydrophobic signals are primarily derived from lipid components like cholesterol, leading to the production of glucocorticoids and steroid hormones such as progesterone and androgens.

• These lipid-derived molecules can travel long distances through the bloodstream, acting on distant cells with specific cytoplasmic or nuclear receptors.

• Upon entering the cell, these small uncharged molecules interact with proteins that undergo structural changes to function as transcription factors.

Transcription Factor Activation

• A glucocorticoid binds to its receptor, causing it to dissociate from a protective chaperone and expose a nuclear localization signal for entry into the nucleus.

• Inside the nucleus, the receptor acts as a transcription factor by binding DNA regulatory sequences to induce specific gene expression.

• The activated receptor not only induces gene expression but also remodels chromatin structure for enhanced transcriptional activity.

Types of Endocrine Signaling

Integrins in Cell-Matrix Interaction

• Integrins serve as structural membrane proteins that anchor cells to extracellular matrices while also facilitating intracellular signaling pathways.

• They modulate interactions between plasma membranes and matrices, influencing cellular responses through phosphorylation of adapter proteins.

Ephrin-Eph Receptor Signaling

• Ephrin receptors mediate dual signaling based on cell-cell interactions; they respond differently depending on whether they are engaged with their ligands across adjacent cells.

Signaling Pathways and Lipid Rafts in Cellular Communication

Overview of Signaling Mechanisms

• Proteins are initially produced in the reticulum as signaling pathways for proteins exposed on the extracellular side of the plasma membrane, acting as receptor tyrosine kinases with transmembrane passage.

• Signals can be characterized functionally (regulating cellular functions like cytoskeleton, metabolic pathways, gene expression) or topologically (how structures receive signals).

Lipid Rafts and Their Role in Signaling

• Lipid rafts are microdomains within membranes that concentrate various phospholipids and proteins to enhance signaling phenomena.

• These lipid rafts contain distinct concentrations of glycolipids, sphingomyelin, and cholesterol, affecting membrane fluidity and receptor concentration for optimized signaling.

• Lipid rafts resist dissolution by non-ionic detergents, allowing controlled purification; caveolae serve as examples of lipid raft-mediated internalization enhancing signaling molecule incorporation.

Regulation Through Lipid Raft Dynamics

• The density of lipids and proteins within lipid rafts allows for differential regulation of signaling systems by controlling protein access based on their affinity to these regions.

• This segregation enables precise interactions between components, leading to a more complex regulatory mechanism for signal transduction.

Interconnectedness of Signaling Pathways

• Although signaling pathways are often described separately for educational purposes, they are typically interconnected and diversified across mechanisms which enhances regulatory complexity.

• A single signal can activate different pathways depending on receptor concentration and cellular readiness, illustrating how cells modulate responses through interconnected networks.

Examples of Signal Modulation

• Various signals interact through similar or distinct pathways affecting different receptors; this modulation is crucial for regulating transcription factors that ultimately change gene expression.

• Signals can also influence cytoplasmic components like mitochondria or cytoskeletal remodeling without directly altering gene expression.

Case Study: Estrogens and PTH Hormone Interaction

• Different cell types generate unique signaling pathways that modulate processes such as maturation, activation, or apoptosis based on shared signals like estrogens and parathyroid hormone (PTH).

Signaling Mechanisms in Bone Remodeling

Autocrine and Paracrine Signaling in Bone Cells

• The signaling pathway involves autocrine signaling where the cell modulates fiber resorption through receptor interactions on its membrane.

• Both parathyroid hormone and estrogen regulate bone matrix production and resorption, indicating a dynamic system dependent on these hormones.

• Parathyroid hormone acts on membrane receptors to stimulate RANK ligand production, which is crucial for bone resorption processes.

• Estrogens promote matrix production by inducing OPG synthesis, which acts autocrinely to inhibit RANK ligand activity, thus reducing bone resorption.

• Osteoclasts are key cells that degrade bone matrix through lysosomal secretion, activated by paracrine signaling from RANK ligand interactions.

Cellular Signaling and Cancer Development

• The transition from normal to malignant cells involves disrupted intracellular signaling pathways that fail to respond appropriately to external signals.

• Alterations in proto-oncogenes can lead to their transformation into oncogenes, promoting uncontrolled cell proliferation associated with tumor growth.

• Growth factors activate receptor tyrosine kinases (RTKs), initiating cascades that amplify signals leading to transcription factor activation and gene expression changes.

• Overactivation of RTKs can result in excessive cyclin D expression, pushing the cell cycle forward uncontrollably without proper regulatory signals.

Growth Factors and Cellular Differentiation

Understanding Growth Factors

• Growth factors are essential for progression in cellular signaling, involving receptors and signaling cascades that lead to the production of cyclin D, which perpetuates self-activation through increased cyclin production.

• It is crucial to differentiate between growth factors and transcription factors; while growth factors induce cell proliferation, transcription factors bind to DNA to regulate gene expression.

Mechanisms of Cell Proliferation

• The activation of a receptor tyrosine kinase initiates signaling cascades (e.g., Ras-MAPK pathway or PI3K-AKT pathway), mediating both proliferation and differentiation processes in cells.

• During development, cells transition from a single-cell stage (zygote) to multicellular systems, initially proliferating with minimal differentiation before undergoing asymmetric divisions leading to specialized functions.

Differentiation Processes

• As differentiation progresses, cells begin acquiring distinct identities and specialized functions through differential gene expression from the same genome.

• Increased differentiation reduces proliferative capacity; terminally differentiated cells lose their ability to divide.

Identity and Determination in Cells

• The process of differentiation involves the expression of specific transcription factors that can create unique cellular identities through asymmetric division.

• A cell's identity is determined by its environment; if it adapts to a new region without losing its original characteristics, it is considered determined.

Gene Expression Regulation

• The maintenance of differentiated states relies on stable gene expression patterns influenced by received signals.

• If a cell maintains its original characteristics after being transferred to another environment, it indicates determination; otherwise, it remains undetermined.

Morphogens and Cellular Specification

• For cells to commit to specific phenotypes, they require sustained differential gene expression based on environmental signals.

Understanding Morphogens and Cell Differentiation

The Role of Morphogens in Cellular Specification

• A single morphogen signal can lead to different cellular specifications based on its concentration and the proximity of the receiving cell.

• Morphogens are substances secreted by a group of cells into the environment, establishing a concentration gradient that regulates differential gene expression in target cells.

• High concentrations of morphogens activate genes A and B consistently, while lower concentrations may only activate one or none, demonstrating how varying levels influence gene regulation.

Mechanisms of Gene Activation

• In low morphogen environments, specific genes remain inactive, altering which transcription factors can be released for gene activation.

• The combination of receptor quantity and the ability to undergo symmetric or asymmetric divisions influences not just maintenance but also differentiation processes in stem cells.

Asymmetric vs. Symmetric Division

• Asymmetric division allows one cell to remain a stem cell while another begins differentiation; symmetric division maintains two stem cells.

• The cytoskeleton structure and extracellular signals play crucial roles in selectively segregating transcription factors within the cell.

Types of Stem Cells

• Totipotent stem cells (e.g., zygotes) can generate all cell types necessary for an organism's development along with supportive structures.

• Pluripotent stem cells cannot form extraembryonic tissues but can differentiate into various cell types; multipotent stem cells exist in specific regions for tissue recovery.

Conclusion and Further Discussion