Cell Signaling Pathways: A Comprehensive Overview
Signaling: Long Range vs. Local Cell Signaling
Long Range Signaling:
Hormones diffuse through the bloodstream, reaching distant target cells.
Signaling molecule acts on a target cell far from the signaling cell, such as endocrine signaling where hormones travel throughout the body.
Examples include insulin produced in the pancreas affecting glucose uptake in muscle cells, or estrogen produced in the ovaries affecting cells in the uterus.
Local Signaling:
Cells close to each other communicate using signals that act locally.
Includes paracrine, autocrine, synaptic, and contact-dependent signaling.
Synaptic Signaling
Cell-to-cell communication between neurons or between a neuron and a target cell (e.g., muscle cell).
A neuron releases neurotransmitters into the synapse that bind to receptors on the target cell, triggering a rapid and localized response.
Neurotransmitters such as acetylcholine or glutamate are released from the presynaptic neuron and bind to receptors on the postsynaptic cell, leading to ion channel opening or other cellular changes.
Endocrine Signaling
Communication occurs when hormones are released into the bloodstream by endocrine glands and travel to target cells throughout the body.
Hormones like adrenaline or cortisol are secreted by the adrenal glands and affect various tissues and organs, regulating metabolism and stress responses.
Differences Between Synaptic and Endocrine Signaling
Endocrine:
Slower, more widespread response due to the time it takes for hormones to travel through the bloodstream.
Signals travel through the bloodstream to reach target cells.
Affects cells throughout the body that express the appropriate receptors.
Duration of effect can be longer-lasting compared to synaptic signaling.
Synaptic:
Signal travels across a small gap (synapse).
Short distance, allowing for rapid and precise communication.
Highly specific, only targets the cell the neuron is directly connected with.
Effects are typically short-lived due to rapid neurotransmitter degradation or reuptake.
Paracrine Signaling
Cell-to-cell communication where a cell releases a signal molecule (paracrine factor) into the extracellular fluid, which diffuses to nearby cells and binds to their receptors.
Regulates cellular activity and coordinates response within a tissue; important in development and tissue repair.
Examples include growth factors secreted by cells promoting proliferation and differentiation in adjacent cells.
Contact-Dependent Signaling
Two cells are in direct contact with each other.
A signal molecule on the surface of one cell binds to a receptor on the surface of the other, triggering a response.
Very specific as it requires physical contact between the signaling and target cells.
Important in immune cell interactions and development, where cell fate decisions are influenced by direct contact.
Differences Between Contact-Dependent and Paracrine Signaling
Paracrine is less specific as the paracrine factors can affect multiple nearby cells that have the appropriate receptors within a certain radius.
Contact-dependent signaling can only occur between cells in direct contact, ensuring precise signaling between adjacent cells.
Autocrine Signaling
Type of paracrine signaling where cells that bind the ligand are induced to express the ligand, creating a positive feedback loop.
Positive feedback loop that increases expression of ligand in the local area, enhancing the signaling effect.
Common in immune cells and cancer cells, where the cell stimulates its own growth and survival.
An example is a cancer cell producing growth factors, which then bind to receptors on the same cell, promoting proliferation.
Signaling Pathways (Examples)
A) Ligand diffuses freely in and out of cells once it is made: Endocrine
B) Activated by cell-cell contact: Contact dependent
C) Activated by mechanical stress on the cell: MAP kinase; mechanical signals transduced into biochemical signals
D) Ligand activation of pathway switches a transcription factor from a repressor form to an activator form: Hedgehog; morphogen gradients regulating development
Hydrophobic vs. Hydrophilic Molecules
Hydrophilic Signal Molecules:
Includes peptides, proteins, and charged molecules.
Cannot cross the target cell's membrane and require cell-surface receptors to transmit signals inside the target cells.
These molecules bind to receptors on the cell surface, which then activate intracellular signaling pathways.
Hydrophobic Molecules:
Includes steroid hormones, thyroid hormones, and gases like nitric oxide.
Can diffuse across the target cell membrane to bind to intracellular receptors.
These molecules often regulate gene expression directly.
Cell Surface vs. Intracellular Receptors
Cell Surface Receptors:
Bind hydrophilic signal molecules that cannot cross the membrane, converting the extracellular signal to intracellular signals.
Examples include G-protein coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs).
Intracellular Receptors:
Bind to hydrophobic signal molecules that can cross the membrane, forming a complex that binds DNA and regulates gene expression.
Located in the cytoplasm or nucleus.
Examples include steroid hormone receptors and nuclear receptors.
Simple Intracellular Signaling Pathway
Signal molecule binds to a receptor protein on the membrane of the target cell, causing a conformational change.
Receptor activates intracellular signaling pathway, often involving a cascade of protein modifications and second messengers.
Intracellular signaling proteins alter the activity of effector proteins, thus changing cell behavior, such as altering gene expression, metabolism, or cell shape.
Combinatorial Signaling
Different signaling molecules, receptors, and signaling pathways interact to produce a specific cellular response.
The same signal molecule can have different effects on different cell types, depending on the combination of receptors and intracellular signaling proteins present.
Steroid Receptor Family
All steroid receptor family members are finger proteins and bind as dimers to specific DNA sequences.
3 modular parts of the steroid receptor superfamily:
Hormone/ligand binding domain: Binds the steroid hormone with high affinity.
DNA binding domain: Contains zinc finger motifs that bind to specific DNA sequences called hormone response elements (HREs).
Transcription activating domain: Interacts with other proteins to regulate gene transcription.
Glucocorticoid vs. Thyroid Receptor Activation
Glucocorticoid:
Hormone (e.g., cortisol) can diffuse into the cell once released from carrier protein in the bloodstream.
Two steroid receptors (glucocorticoid receptors) work together to activate transcription by binding to glucocorticoid response elements (GREs) in DNA.
In the absence of hormone, the receptor is typically bound to chaperone proteins in the cytoplasm.
Thyroid:
Ligand (thyroid hormone) diffuses through cell/membrane and binds thyroid receptor to activate transcription.
Repressor when on DNA in the absence of ligand, acting as an activator when ligand is bound.
Thyroid hormone receptor typically forms a heterodimer with retinoid X receptor (RXR) on thyroid hormone response elements (TREs).
Sex Steroids
Produced by gonads (synthesized from cholesterol).
Testosterone - male development/maintenance, including muscle growth and bone density.
Estrogen - female development/maintenance, including regulation of menstrual cycle and bone health.
Progesterone - pregnancy and nursing, plays a key role in preparing the uterus for implantation and maintaining pregnancy.
Corticosteroids
Produced by adrenal gland
Glucocorticoids (including cortisol) - stimulate the production of glucose, regulate immune responses, and help the body respond to stress.
Mineralocorticoids (e.g., aldosterone) - act on the kidney to regulate salt and water balance, maintaining blood pressure and electrolyte balance.
Other Hormones
Thyroid hormone: regulates metabolism, affecting energy expenditure and growth.
Retinoids: regulate vertebrate development, influencing cell differentiation and morphogenesis.
Vitamin D3:
Produced by skin, processed in the kidney; requires UV light to synthesize.
Function: Regulation of metabolism and bone growth; essential for calcium absorption in the intestine.
Absence leads to rickets - softening of bones so that they bend and cannot support body weight; can also cause muscle weakness and developmental delays.
Lipid Soluble Hormones
Examples: testosterone, cortisol, retinoic acid
Key characteristics: all small and hydrophobic, no side chain means no carbon-carbon interactions, allowing them to easily diffuse across cell membranes.
Early Primary Response vs. Delayed Secondary Response to Steroid Hormones
Primary:
Involves regulation of existing proteins and rapid changes in gene expression.
Involves activation of signaling pathways like MAPK, leading to immediate cellular responses.
Primary response genes are rapidly transcribed and translated.
Delayed Secondary:
Primary response protein shuts off primary response gene and turns on secondary response genes, creating a cascade of gene expression changes.
Involves transcription of new genes that lead to the synthesis of new proteins, resulting in longer-term changes in cell behavior.
Involves activation of gene transcription by steroid hormone receptors, leading to sustained cellular responses.
Synthesis of Nitric Oxide (NO)
Its a gas and a free radical with a short half-life.
Made by nitric oxide synthase (NOS) from arginine through a complex enzymatic reaction.
Can diffuse through the membrane easily, allowing it to act locally.
Mechanism of Action of Nitric Oxide
NO activates guanylate cyclase to increase cGMP content, which activates PKG, leading to smooth muscle relaxation and vasodilation.
cGMP acts as a second messenger.
Viagra
Viagra increases NO response by preventing the decrease in cGMP by inhibiting phosphodiesterase type 5 (PDE5), which normally breaks down cGMP.
Prolonged cGMP levels enhance smooth muscle relaxation, improving blood flow.
Nitric Oxide entry into cells and second messenger
A) Enters cells through the plasma membrane by passive diffusion due to its small size and lipophilic nature and can also be actively transported by specific transporters in some cell types.
B) cGMP: Cyclic GMP is the primary second messenger activated by NO.
C) Phosphodiesterases: Enzymes that degrade cGMP, terminating the NO signal.
Other Purposes of Nitric Oxide
Macrophages use NO + O2 to make ONOO- to kill invading cells, acting as a potent antimicrobial agent.
Memory: long-term potentiation involves NO signaling in neurons, enhancing synaptic plasticity.
NO given to COVID patients to increase blood flow in lungs, improving oxygenation.
G-Protein Linked Receptor
Seven transmembrane alpha helices spanning the cell membrane.
N terminus () located extracellularly binds ligand, initiating the signaling cascade.
Loops on inside interact with G proteins, facilitating the activation of downstream signaling pathways.
G-Proteins
All G-proteins are active when bound to GTP and inactive when bound to GDP, acting as molecular switches.
The exchange of GDP for GTP is catalyzed by guanine nucleotide exchange factors (GEFs).
Monomeric vs. Trimeric G-Proteins
Monomeric:
No receptor, activated directly by GEFs.
Activated by GEF, which promotes the exchange of GDP for GTP.
Inactivated by GAP, which stimulates GTP hydrolysis.
Examples include Ras and Rho family proteins.
Trimeric:
Has receptor (GPCR); activated by the receptor ligand-binding.
Activated by the receptor ligand-binding, leading to the dissociation of Gα from Gβγ subunits.
Always bound to the membrane via lipid anchors.
Consist of α, β, and γ subunits.
Monomeric G-Protein Pathway
Ligand binds and activates GPCR on cell surface, exchanging GDP for GTP (conformational change).
Signal transduction: interacts with adenylyl cyclase, generating second messengers like cAMP or IP3, modulating cellular activity.
Second messengers activate downstream signaling pathways that lead to cellular behavior changes, such as altering gene expression or ion channel activity.
G-protein deactivated by GAPs or GEFs that help hydrolyze the bound GTP to GDP, returning the G-protein to its inactive state.
Second messengers : cAMP and IP3
Trimeric G-Protein Pathway
Binding of hormone (signaling molecule) causes a conformation change in the receptor, enabling it to interact with the G-protein.
Activated receptor (GEF) binds to g-protein alpha subunit, facilitating nucleotide exchange.
Binding induces conf change in g alpha, bound GDP replaced by GTP, dissociates from g- beta and gamma, activating downstream effectors.
Hormone dissociates from receptor -> g-protein alpha binds to effector (GAP) activating it, triggering cellular responses.
Hydrolysis of GTP to GDP causes g alpha to dissociate from effector and reassociate with beta-gamma, terminating the signal.
Adenylyl Cyclase
Adenylyl cyclase is an effector that interacts with Gs (stimulatory) and G alpha G-protein coupled receptors, converting ATP to cAMP.
cAMP then activates protein kinase A (PKA), leading to phosphorylation of target proteins.
Signaling Pathways (Examples)
A) Cell surface receptor itself is cleaved to generate a transcription factor: Notch signaling; proteolytic cleavage releases the intracellular domain, which translocates to the nucleus.
B) Ligand for a signaling pathway that is a gas: NO; diffuses across cell membranes and activates guanylate cyclase.
C) Signaling pathway in which a downstream transcription factor is constantly being degraded in the absence of ligand: Wnt; β-catenin is degraded in the absence of Wnt signaling.
D) Signaling pathway that assembles an activated dimeric transcription factor at the receptor: Jak Stat; receptor-associated kinases activate STAT transcription factors, which dimerize and translocate to the nucleus.
How a rise in intracellular cAMP conc. can alter gene transcription
Extracellular signal molecule binds to GPCR -> activates adenyl cyclase -> increases cAMP -> activates PKA -> PKA phosphorylates CREB -> recruits CBP which stimulates gene transcription.
Occurs on CRE (cAMP response element in DNA), leading to increased gene expression.
Adrenergic Receptors
Alpha - contraction of blood vessels, increases blood pressure.
Beta - dilation of blood vessels, decreases blood pressure.
These receptors bind to adrenaline and noradrenaline and mediate the fight-or-flight response.
G-Protein-Linked Second-Messenger Signaling Pathway
First messenger binds to and activates a membrane receptor, such as a GPCR.
Gs protein associates with the activated receptor, becoming activated.
GDP dissociates from Gs protein, allowing GTP to bind.
GTP binds to Gs protein, causing a conformational change.
Gs protein dissociates into α and β /γ subunits, activating downstream effectors.
α subunit of Gs protein binds to and activates adenylate cyclase, stimulating cAMP production.
Many molecules of cAMP are produced, amplifying the signal.
GTP is hydrolyzed to GDP, inactivating the α subunit.
Activation of adenylate cyclase ends, terminating cAMP production.
Synthesis and Degradation of cAMP
Catalyzed by the enzyme adenylyl cyclase, cAMP is synthesized from ATP through a reaction that removes two phosphate groups, forming a cyclic structure.
A pyrophosphatase drives the reaction by hydrolyzing the released pyrophosphate to phosphate, ensuring the reaction proceeds efficiently.
cAMP Instability
Cyclic AMP is short-lived (unstable) in the cell because it is hydrolyzed by specific phosphodiesterases to form 5′-AMP, terminating the signal.
This rapid degradation allows for precise control of cAMP levels and cellular responses.
Phosphodiesterase Inhibitor Consequences
There would be an increase in cAMP because it is not turning into AMP (which phosphodiesterase does), and PKA would still increase would cause cell function to continue, leading to prolonged signaling.
Examples include caffeine and theophylline, which inhibit phosphodiesterases and prolong cAMP signaling.
Activation of Protein Kinase A (PKA)
cAMP binds to its regulatory subunits, causing a conformational change that releases the catalytic subunits and activates PKA.
Activated PKA can then phosphorylate target proteins, altering their activity.
Target of A Kinase
Phosphorylates CREB, which activates it, allowing it to bind to DNA and regulate gene transcription.
CREB phosphorylation enhances its interaction with transcriptional co-activators.
Activated CREB
After PKA phosphorylates it, it acts as a TF that binds the cAMP response element upstream of genes and activates transcription through CBP/P300, which has histone acetyltransferase activity.
CREB recruits histone acetyltransferases to open chromatin and promote gene expression.
CBP/P300 Activity
Histone acetyltransferase activity acetylates lysine residues on histone tails, leading to chromatin remodeling and increased gene transcription.
CBP/P300 also interacts with other transcription factors to regulate gene expression.
Receptor Desensitization
Receptor desensitization makes cell responsive to an increase in ligand concentrations, preventing overstimulation.
This process involves mechanisms such as phosphorylation, internalization, and downregulation of receptors.
Beta-Adrenergic Receptors
Bind to epinephrine and norepinephrine, mediating the fight-or-flight response.
These receptors are GPCRs that activate adenylyl cyclase and increase cAMP levels.
Receptor Desensitization Pathway for G-Protein-Coupled Receptors
Ligand binds to receptor and activates G protein, initiating the signaling cascade.
G protein activates effector protein, such as adenylyl cyclase or phospholipase C.
Second messenger produced (cAMP or IP3) which amplifies the signal and triggers downstream responses.
Prolonged exposure to ligand causes phosphorylation of receptor by kinase(GRK), reducing its ability to activate G proteins.
Receptor binds to arrestin, further reducing its signaling capacity.
Beta-arrestin blocks the ability of G protein to activate effector, resulting in a reduction in signaling, and promotes receptor internalization.
Beta-Adrenergic Receptor Desensitization Mechanisms
Cells become less responsive to the stimulation of beta-adrenergic receptors due to constant exposure of high levels of epinephrine or norepinephrine, decreasing their physiological effects.
Prolonged activation leads to receptor phosphorylation, arrestin binding, and receptor internalization, reducing the number of receptors on the cell surface.
GPCR kinase binds ligand and conformation changes because there are seven transmembranes inside can now interact with trimeric G-protein, initiating signaling.
Phosphorylated by RTK arrestin binds and shut it down completely, preventing further signaling.
Role of GPCR Kinases and Arrestins in GPCR Desensitization
A GRK phosphorylates only activated receptors because it is the activated GPCR that turns on the GRK, providing specificity.
The binding of an arrestin to the phosphorylated receptor prevents the receptor from binding to its G protein, sterically hindering the interaction.
Mice deficient in one form of arrestin fail to desensitize in response to morphine, attesting to the importance of arrestins for desensitization and drug tolerance.
Breakdown of PIP2
Generates two second messengers:
IP3: releases intracellular from the endoplasmic reticulum.
DAG: activates Protein Kinase C (PKC), phosphorylating target proteins.
The hydrolysis of PIP2 is a crucial step in the activation of many signaling pathways, including the Gq pathway, which is activated by GPCRs and PLC.
Gq Pathway
What happens after GPCR cleaves PIP2 to increase cytosolic and activate PKC:
Ligand binds to a GPCR and activates the G protein which activates PLC, initiating the signaling cascade.
PLC cleaves PIP2 -> IP3 and DAG, generating two key second messengers.
IP3 diffuses into cytosol -> binds to and opens channels on the ER membrane, releasing calcium into the cytoplasm.
DAG remains associated with plasma membrane and activates PKC by binding to C1 domain, phosphorylating target proteins.
Activated PKC phosphorylates target proteins, leading to various cellular responses.
Active vs. Inactive PKC
Active: PKC phosphorylates IK-B -> changes its conformation -> goes into the nucleus and acts as a TF -> promoting transcription of target genes.
Inactive: Without phosphorylation, PKC remains inactive and unable to phosphorylate its targets.
Calmodulin
Calmodulin is activated by the binding of , undergoing a conformational change that allows it to interact with target proteins.
The -calmodulin complex regulates a variety of cellular processes.
Ca+2/Calmodulin Complex
It activates what 3 CaM-kinases:
Myosin light-chain kinase activates smooth muscle contraction by phosphorylating myosin light chains.
Phosphorylase kinase activates glycogen breakdown by phosphorylating glycogen phosphorylase.
CaM kinase II increases neurotransmitter synthesis & secretion, affecting neuronal signaling and synaptic plasticity.
The /calomodulin complex is a short-lived, second messenger that rapidly responds to changes in intracellular calcium levels.
Rod Cells
When it's dark:
Depolarized: Rod cells are depolarized in the dark due to open sodium channels.
Rhodopsin is inactive: Rhodopsin is not activated by light.
Sodium channels are open, which continuously send a signal, resulting in a constant influx of sodium ions.
High rate of neurotransmitter release: Rod cells continuously release neurotransmitters like glutamate.
When it's light:
Hyperpolarized: Light activation causes hyperpolarization of rod cells.
Rhodopsin is activated: Rhodopsin absorbs photons and undergoes a conformational change.
Sodium channels are closed, reducing sodium influx.
Low rate of neurotransmitter release: Rod cells release less neurotransmitter.
Response of a Rod Photoreceptor Cell to Light
Rhodopsin molecules absorb photons, which closes cation channels in the plasma membrane, reducing ion flow.
Membrane hyperpolarized -> rate of neurotransmitter reduced, altering signal transmission to downstream neurons.
Illumination frees the neurons from inhibition & excites them, allowing visual signals to be processed.
Light passes through synapses and rod cell nucleus to reach light sensors, maximizing photon capture.
Rhodopsin mechanism
Light-activated rhodopsin activates Gt to activate PDE -> converts cGMP to GMP -> Na+ channels close -> hyperpolarizes neuron -> signal not sent to brain.
Gt (transducin): Activates cGMP PDE in rod photoreceptors, initiating the phototransduction cascade.
When rhodopsin absorbs a photon, the conformational change activates transducin, amplifying the light signal.
The amplification of the light-induced signal in rod cells occurs due to the presence of many copies of rhodopsin and transducin within each rod cell, ensuring high sensitivity.
Receptor Tyrosine Kinases
Receptor tyrosine kinases are cell-membrane receptors that bind ligands on the outside of the cell and activate intracellular signaling pathways.
These receptors play critical roles in cell growth, differentiation, and survival.
Ligand for Rhodopsin Gta-mediated signaling
Retinal (derived from vit A) is the chromophore that absorbs light and initiates the phototransduction cascade in rhodopsin.
Retinal undergoes isomerization from cis to trans form upon light absorption.
Structure of Receptor Tyrosine Kinases
Single pass transmembrane domain anchors the receptor in the cell membrane.
Intracellular tyrosine kinase domain phosphorylates tyrosine residues on target proteins, initiating downstream signaling cascades.
Function of Receptor Tyrosine Kinase
Receptor tyrosine kinase will dimerize upon ligand binding and cross-phosphorylate each other, activating the kinase domains.
This is called as cross-phosphorylation because they phosphorylate the same type receptor as themselves, enhancing signaling efficiency.
Dimeric or Multimeric Ligands/Signal Proteins
Act via receptor tyrosine kinases, promoting receptor dimerization and activation.
PDGF (Platelet-Derived Growth Factor)
FGF (Fibroblast Growth Factor)
Eph (Ephrin)
Signaling Proteins
Signaling proteins that contain SH2 domain & PTB domain are recruited to phospho-tyrosine residues to activate multiple signaling pathways.
SH2 domains bind phosphorylated tyrosine residues on activated receptors.
PTB domains also bind phosphorylated tyrosine residues with specific sequence context.
Phospholipase Cγ
Phospholipase Cγ is activated by binding RTK dimers, leading to the hydrolysis of PIP2 and the generation of IP3 and DAG.
PLCγ activation is essential for calcium signaling and PKC activation.
Activation of RAS
Activation of RAS is the first step in activating the MAPK pathway, which regulates cell growth, differentiation, and survival.
Activation of RAS by RTK is not direct but requires a separate adaptor & GEF(guanosine exchange factor), ensuring precise regulation.
RAS G-protein binds to GTP or GDP, being ACTIVE ONLY when bound to GTP.
Ras requires assistance from a guanine-nucleotide exchange factor (GEF) called SOS to acquire a GTP molecule, activating RAS.
MAPK Pathway
The first protein phosphorylated is RAF, a protein kinase that initiates the MAPK cascade.
Raf will phosphorylate ser(serine) & thr(threonine) residues in a protein kinase called MEK, activating its kinase activity.
MEK in turn phosphorylates ser & thr residues in a class of proteins called mitogen-activated protein kinases (MAPKs), further propagating the signal.
MAPKs will phosphorylate transcription factors that enter the nucleus to alter gene expression, regulating cell growth, differentiation, and survival.
RAS-MAPK Pathway
The RAS-MAPK pathway uses tyrosine kinases that phosphorylate each other in a sequential manner, amplifying the signal.
This pathway is highly conserved and plays a crucial role in development and cancer.
Ras-MAPK Signaling pathway
Ligand binds, receptor dimerises, promoting receptor activation.
RTK autophosphorylation creates docking sites for signaling proteins.
GRB2 (SH2 domain containing protein) recognises phosphotyrosine residues, initiating RAS activation.
GRB2 recruits SOS, bringing it to the plasma membrane.
SOS activates RAS, GDP exchange for GTP, activating RAS.
RAS recruits RAF-1 and activates it, initiating the MAPK cascade.
RAF-1 phosphorylates and activates MEK, further propagating the signal.
MEK phosphorylates and activates MAPK, activating its kinase activity.
MAPK phosphorylates cellular proteins e.g. transcription factors, altering gene expression and cell behavior.
Grb (growth factor receptor-bound protein)
Grb binds P-Tyr and has 1 SH2 and 2 SH3 domains, mediating protein-protein interactions.
SH3 domains bind Proline-rich motifs, facilitating the assembly of signaling complexes.
MAP Kinase Cascade
MAPKs phosphorylate TFs in the nucleus, which then bind to specific DNA sequences and regulate transcription of target genes, altering cell behavior.
MAPKKK activates MAPKK activates MAPK (via phosphorylation), creating a signaling cascade that amplifies the signal.
PI 3-Kinase Pathway
Important in countering apoptosis in healthy cells and promotes cell survival, protecting cells from programmed cell death.
PI3-kinase is activated by RTKs, initiating the PI3K/Akt signaling pathway.
PI3 kinase phosphorylates PIP2 » PIP3, creating a docking site for Akt kinase.
PI3 kinase can activate Akt kinase, a key regulator of cell survival and growth.
PI3K/Akt Pathway in Cancer Cells
Often overactivated in cancer cells, leading to increased cell survival and proliferation, due to Akt kinase promoting cell growth and survival by inhibiting apoptotic pathways and activating cell cycle progression.
3 Ser/Thr kinases: Akt, Pdk1, mTor, regulate cell growth, proliferation, and survival.
JAK-STAT Pathway
Core signals:
Ligand binds cytokine receptors, initiating receptor dimerization and activation.
Dimerization and phosphorylation of tyrosines, creating docking sites for STAT proteins.
Phosphorylation of additional tyrosine residues, further enhancing STAT activation.
STAT SH2 and DNA binding domain disassociate, allowing STATs to dimerize.
SH2/DNA domains of STAT dimerize, forming active transcription factors.
Dimer into the nucleus to activate transcription, altering gene expression.
TGF-beta Pathway
Purpose: Angiogenesis, fibrosis, cell cycle arrest, regulating tissue development and repair.
Receptors: Uses a Type 1 and Type 2 receptor (does not use G-proteins), forming a heterotetrameric complex.
Type 1 binds TGF-B poorly and Type 2 binds it tightly, initiating signaling.
TGF-beta signaling assembles SMAD transcription factor complexes, which regulate gene expression.
Notch Signaling
Type of signaling: allows cells to signal to neighboring cells via direct cell to cell interaction, regulating cell fate decisions.
Overexpressed in cancer, promoting tumor growth and metastasis.
Similarities Between Notch, Wnt, and Hedgehog Signaling Pathways
Have similar functions in embryonic development and tissue regeneration in adults, regulating cell differentiation and tissue patterning.
Aberrant activation of these pathways is associated with various diseases, including cancer.
Therapeutics targeting Notch / Wnt signalling/ Hedgehog pathways
Drugs are being invented to block these pathways to prevent overexpression as seen in the cancer phenotype, offering potential therapeutic strategies.
These therapies aim to inhibit tumor growth and metastasis.
Wnt Signaling
Controls b-catenin transcription factor degradation, regulating gene expression.
With Wnt signal - transcription; without - no transcription, controlling cell fate and differentiation.
Hedgehog Signaling
Switches Ci transcriptional repressors & activators, modulating gene expression.
With vs without hedgehog signaling, determining cell fate and tissue patterning.
If the SHH gene is mutated or absent, the protein Sonic Hedgehog cannot do its job properly, leading to developmental defects.
Sonic hedgehog contributes to cell growth, cell specification and formation, structuring and organization of the body plan, particularly during embryogenesis.
When Sonic Hedgehog (Shh) is added: smoothened (Smo) moves to primary cilia, activating downstream signaling.
Location: primary cilia, where Smo accumulates upon Shh binding.
Summary of Signaling Pathways
One signal transduction pathway that degrades (to completely destroy) a transcription factor when a ligand is not present: Wnt,
The GPCR-linked pathways discussed in the notes are:
Adenylyl Cyclase Pathway: This pathway involves Gs (stimulatory) and G alpha G-protein coupled receptors, which convert ATP to cAMP. cAMP then activates protein kinase A (PKA), leading to phosphorylation of target proteins.
Receptor Desensitization Pathway: This pathway involves GRK phosphorylation of the receptor and arrestin binding, reducing the receptor's ability to activate G proteins.
Gq Pathway: In this pathway, GPCR activates