SIGNAL TRANSDUCTION PATHWAYS AND THE CELL CYCLE Flashcards
Cell communication controls a variety of functions, including:
•- cell activation
•- cell differentiation
•-cell death
•Loss of effective cellular communication can potentially lead to unregulated growth (cancer) or inappropriate response to stress (shock).
Cells can respond to the following extrinsic signals:
- Pathogens and damage to neighbouring cells
-Contacts with neighbouring cells, mediated through adhesion molecules and/or gap junctions.
-Contact with ECM, mediated through integrins
-Secreted mmolecules, e.g. growth factors, cytokines, and hormones.
CLASSIFICATION OF CELL-CELL SIGNALING PATHWAYS
•PARACRINE: Paracrine cell signaling is a type of cell signaling where cells communicate with neighboring cells through signaling molecules, without releasing these molecules into the bloodstream.
•AUTOCRINE: Autocrine pathway refers to a type of cell signaling where a cell produces and responds to its own signaling molecules, such as hormones or growth factors.
•SYNAPTIC: Synaptic pathway: A type of cell signaling where chemical signals (neurotransmitters) are transmitted between two neurons through a synapse, allowing them to communicate and coordinate their activities.
•ENDOCRINE: Endocrine pathway: A type of cell signaling where cells produce and release hormones into the bloodstream, which then travel to reach and affect distant target cells or organs.
Ligands in cell signaling
Signaling molecules called ligands bind to their respective specific receptors to initiate a cascade of intracellular events.
Receptors can be:
A. Intracellular receptors – transcription factors activated by lipid soluble ligands that readily cross plasma membrane, e.g. vit. D and steroid hormone, which bind and activate nuclear receptors to drive specific gene transcription.
B. Cell-surface receptors:
These are generally transmembrane proteins with extracellular ligand-binding domains.
Ways in which Ligand binding occurs
-Open ion-channels (e.g. the synapse betewen electrically excitable cells)
-Activate an associated guanosine triphosphate (GTP)-binding regulatory protein (G-protein).
-Activate an endogenous or associated enzyme, often a tyrosine kinase
Ligand binding to surface receptors mediate signaling by:
•-inducing clustering of receptors (receptor cross-linking)
•-by other types of physical peturbations.
These trigger intracellular biochemical changes, ultimately activating transcription factors that enter the nucleus to alter gene expression.
Five main pathways of signal transduction
•1. Receptor associated with kinase activity
•2. Receptors with no intrinsic catalytic activity (utilizes separate intracellular nonreceptor tyrosine kinases).
•3. G-protein coupled receptors
•4 Nuclear receptors.
•5. Others, e.g.:
•- .Ligand binding to Notch receptors
•- Wnt protein ligands signal through
RECEPTOR ASSOCIATED WITH KINASE ACTIVITY and examples of ligands that bind to these receptors
•Alteration in the receptor geometry elicit intrinsic receptor protein kinase activity or promote the enzymatic activity of recruited intracellular kinases (tyrosine, serine/threonine, and lipid kinases).
•This results in the addition of charged phosphate residues to target molecules
•E.g. Receptor tyrosine kinases (RTKs)- include receptors of insulin, EGF, PDGF
•Phosphatases exist to remove added phosphate residues thus modulating signaling.
What are RECEPTOR TYROSINE KINASES (RTKs) and their mode of action?
*Receptor tyrosine kinases (RTKs) are integral membrane proteins (e.g., receptors for insulin, epidermal growth factor, and platelet derived growth factor);
*Ligand-induced cross-linking activates intrinsic tyrosine kinase domains located in their cytoplasmic tails.
*Typical example is the growth factor receptor/RAS-MAP kinase pathway
Phosphatidyl 3-kinase (PI3K) phosphorylates a membrane phospholipid, generating products that activate the kinase Akt (also referred to as protein kinase B), which is involved in cell proliferation and cell survival through inhibition of apoptosis
Other effector molecules activated by receptors with intrinsic tyrosine kinase activity include phospholipase Cγ (PLCγ) and phosphatidyl inositol-3 kinase (PI3K)
*PLCγ catalyzes the breakdown of membrane inositol phospholipids into inositol 1,4,5-triphosphate (IP3), which functions to increase concentrations of calcium, an important effector molecule, and diacylglycerol, which activates the serine-threonine kinase - protein kinase C that in turn activates various transcription factors.
Binding of the growth factor (ligand) causes receptor dimerization and autophosphorylation of tyrosine residues. Attachment of adapter (or bridging) proteins couples the receptor to inactive, GDP-bound RAS, allowing the GDP to be displaced in favor of GTP and yielding activated RAS. Activated RAS interacts with and activates RAF (also known as MAP kinase kinase kinase). This kinase then phosphorylates
MAPK (mitogen-activated protein kinase) and activated MAP kinase phosphorylates other cytoplasmic proteins and nuclear transcription factors, generating
cellular responses.
RECEPTORS WITH NO INTRINSIC CATALYTIC ACTIVITY
•Several receptors have no intrinsic catalytic activity
•Examples include: immune receptors, some cytokine receptors, and integrins
•Here, separate intracellular proteins called nonreceptor tyrosine kinase (NRTK) phosphorylate specific motifs on the receptors or other proteins.
•E.g. of NRTK is SRC, which contain Src-homology 2 and 3 domains(SH2 & SH3).
The cellular homolog of the transforming protein of the Rous sarcoma virus, called SRC, is the prototype for an important family of such nonreceptor tyrosine kinases -NRTKs (Src-family kinases).
•SRC contains unique functional regions,such as Src-homology 2 (SH2) and Src-homology 3 (SH3) domains.
SH2 domain typically bind to receptors phosphorylated by another kinase, allowing the aggregate of multiple enzyme.
•SH3 domains mediate other protein-protein interactions, often involving proline-rich regions.
•Another family under this group is JAK (Janus kinase) family of proteins – JAK/STAT PATHWAY
What are G-PROTEIN COUPLED RECEPTORS and give examples of ligands that use this receptor
•G-protein coupled receptors are polypeptides that characteristically traverse the plasma membrane seven times.
•A large number of ligands signal through this type of receptor, including chemokines, vasopressin, serotonin, histamine, epinephrine and norepinephrine, calcitonin, glucagon, parathyroid hormone, corticotropin, and rhodopsin.
After ligand binding, the receptor associates with an intracellular G protein that contains GDP
•G-protein interacts with a receptor-ligand complex resulting in activation through the exchange of GDP for GTP.
•Downstream receptor mediated signaling events result in the generation of cyclic AMP (cAMP), and inositol-1,4,5,-triphosphate (IP3), the latter releasing calcium from the endoplasmic reticulum.
Calcium signals, which are generally oscillatory, have multiple targets, including cytoskeletal proteins, chloride- and potassium-activated ion pumps, enzymes such as calpain, and calcium-binding proteins such as calmodulin.
• cAMP activates a more restricted set of targets that include protein kinase A and cAMP-gated ion channels, important in vision and olfactory sensing.
What are NUCLEAR RECEPTORS? Examples of Ligands that bind to such receptors
•Lipid-soluble ligands can diffuse into cells where they interact with intracellular proteins (generally located in the nucleus) to form a receptor-ligand complex that directly binds to nuclear DNA.
•The activated receptor binds to specific DNA sequences known as hormone response elements within target genes, or they can bind to other transcription factors
The results can be either activation or repression of gene transcription
•Ligands that bind to members of this receptor family include steroids, thyroid hormone, vitamin D, and retinoids.
•In addition to steroid hormone receptors, a group of receptors belonging to this family are called peroxisome proliferator-activated receptors
What is a NOTCH FAMILY?
•Ligand binding to Notch receptors leads to proteolytic cleavage of the receptor
•Then there is nuclear translocation of the cytoplasmic piece to form a transcription complex
WNT (FIZZLED FAMILY RECEPTOR)
•Wnt protein ligands can also influence cell development through a pathway involving transmembrane Frizzled family receptors, which regulate the intracellular levels of β-catenin.
•Normally, β-catenin is constantly targeted for ubiquitin-directed proteasome degradation.
However, Wnt protein ligand binding to Frizzled (and other co-receptors) recruits yet another intracellular protein (Disheveled) that leads to disruption of the degradation-targeting complex.
•The stabilized pool of β-catenin molecules then translocates to the nucleus, where β-catenin forms a transcriptional Complex.
