Cell Signaling
The Process of Converting External
Signals into Cell Responses
1) Occurs in Unicellular and Multicellular Organisms
2) Allows for Cells to Respond to their Environment
3) Allows for Communication Between Cells Coordinates Activities of Neighboring Cells C
General Steps in Cell Signaling
Many extracellular signals act via cell-surface receptors to change behavior of target cell
- extracellular signaling molecule binds to receptor protein, intracellular signaling molecules to effector proteins -> target cell responses (metabolic enzyme->al
Types of Cell Signaling Responses
Movement/Secretion/Metabolism
Growth and Cell Div
- through diff intracellular signaling pathways
Fast: Altered protein function (changes in cell movement/secretion/metabolism)
Slow: Altered gene exp (synth of new proteins)
Both: altered cytoplasmic machi
Key Roles of Cell Signaling in Multicellular Organisms
Every cell displays a set of receptor proteins- enable it to respond to specif set of extracellular signal molecules produced by other cells
- signal molecules work in combos to reg cell behavior
- may require multiple signals to survive, addt'l ones to g
A Large Variety of Molecules Can Function as Extracellular Messengers
A Wide Variety of Polypeptides and Proteins
- Transmembrane proteins or secreted proteins
- Cell division, cell differentiation, immune response , cell death and cell survival
� Amino Acids and Amino Acid Derivatives
- Glutamate, acetylcholine, epinephrin
Transport of Signaling Molecules to Target Cells
I.Contact-Dependent Signaling
II.Through the Action of a Secreted Molecule Paracrine
Autocrine
Endocrine
Synaptic
Contact-Dependent Signaling
Does Not Involve Release of Secreted Molecule
Cell-Cell Recognition
Signal Molecule Displayed on Cell Surface of Signaling Cell binds to receptor protein on adjacent cell
Contact Dependent Signaling in Neuronal Development
in embryonic development, allows adj cells initially similar to become specialized/ different
- unspecified epithelial cells undergo specialization and lateral inhibition- each future neuron delivers inhibitory signal to cells next to it, deterring them f
Signaling Involving a Secreted Molecule: Paracrine and Autocrine Signaling
Local Signaling-
Local Mediator Molecules Secreted and Diffuse Through Immediate Environment
Example: Growth Factors That Stimulate Nearby Cells to Grow And Divide
Autocrine
Paracrine
Signaling Involving a Secreted Molecule: Endocrine Signaling
Specialized Type of Long Distance Signaling
Specialized Cells Release Hormone Molecules into the Circulatory System-
Travel to Target Cells In Other Parts of the Body
Hormones: Proteins and Peptides, Amines from Amino Acids and Steroids
Signaling Involving a Secreted Molecule: Synaptic Signaling
Specialized Type of Signaling In Animal Nervous System
Signals Transmitted along Axons to Remote Target Cells
Nerve Cell Releases
Neurotransmitter
Molecules into a Synapse, Stimulating Target Cell
Example: Acetylcholine - diff effects
Signal Transduction Events:
Cascades of Molecular Interactions That Relay Signals from Receptors to Target Molecules in the Cell
Example of Cell Surface Receptor Mediated Signaling
- receptor protein on cell surface transduces extracellular signal into intracellular signal- initiates 1+ intracellular signaling pathways that relay signal into cell interior
- ecah pathway includes in
Response of a Target Cell is Specific
Dependent Upon a Cell's Particular Collection of :
Receptor Proteins Present
Proteins Involved in Relay
Proteins Involved in Carry Out the Response
ex: ACh
- in heart pacemaker cell - decreased firing
- in salivary gland cell - secretion
- in skeletal mus
Cell Signaling Receptors
� Receptors
- I. Intracellular Receptors
- II. Cell Surface Receptors � Ion Channel Receptors
� G protein Coupled Receptors
� Enzyme Coupled Receptors � Gases in Cell Signaling
Two Main Classes of Cell Signaling Receptors
I. Intracellular
II. Cell-Surface Receptor
1. Intracellular Receptors: Ligand Activated Transcription Regulators
Signals: Include Steroid Hormones, Thyroid Hormones All Small Hydrophobic Signaling Molecules
- bc have to get across to membranes- 1st through PM, then nuclear mem or env (through pores)
- elicit response in nucleus and (in)activate transcription
Small Hydrophobic Hormones Diffuse Across the Plasma Membrane and Activate Transcription Regulators That Alter Gene Expression
Fig 16-9
- ex: cortisol, estradiol, testosterone, thyroxine
- can activate diff genes
- cortisol comes through PM
- when binds nuclear receptor protein, changes and activates protein
- activated receptor-cortisol complex can move through pores into nucleu
3 main classes of Cell-Surface Receptors
1. Ion-channel-coupled receptors
- change permeability of PM to selected ions, allow ions to transverse- alter mem potential and produce electrical current
- transmit signals across synapses in NS - transduce NT delivered to outside of target cell into el
G-Protein Coupled Receptors (GPCRs)
- Largest Family of Cell-Surface Receptors
- Diverse Signal Molecules include:
- Peptide Hormones and Neurotransmitters
- Target for drugs (many cell processes)
- Paracrine, Synaptic and Endocrine Signaling
- Receptors: All are Seven Pass Transmembrane Re
Ligand Binding Alters GPCRs Conformation to Permit Binding and Activation of a Trimeric G-Protein
Inactive GDP Bound Form a Complexed
Active GTP Bound From
Dissociate from bg complex
- GRP form is inactive
- alpha, beta, and gamma subunit
- when signal molecule binds, conf change allows GTP to bind to GPCR protein
- phosphorylation event with GTP
- en
G-Protein Subunits Can Activate Membrane Associated Enzymes that Synthesize or Release Second Messengers
Second Messengers: Small and non-protein
Include: Nucleotides(cAMP), Ions (Ca2+), Phospholipid Derivatives (DAG and IP3)
Allow Fast Response:
Rapidly Synthesized and Destroyed (or Released and Removed)
- all due to activated G protein subunit after bound
cAMP is synthesized from ATP and degraded to AMP
G-Proteins Can Stimulate or Inhibit ADENYLYL CYCLASE
1. ATP
- adenylyl cyclase
2. cAMP - formed from ATP by cyclization- removes 2 Ps from ATP and joins free end of remaining P to sugar of AMP- degradation reaction breaks new bond, forming AMP
- cAMP phos
cAMP as a Second Messenger in a G-Protein Signaling Pathway
Skeletal Muscle and Liver Cells
Adrenaline= Epinephrine
PKA = Protein Kinase A
- normally inactive in complex with a regulatory protein
- binding of cAMP to regulatory protein forces conf change that releases inhibition/unleashes active kinase
- activated
Activation of Protein Kinase A (PKA) Can Alter Gene Expression
Binding of signal molecule to its GPCR can lead to activation of adenylyl cyclase and rise in conc of cytosolic cAMP - activates PKA- moves into nucleus and phosphorylates specif transcription regulators - once phosphorylated, proteins stimulate transcrip
G-Protein Coupled Receptors Can Activate Enzyme Phospholipase C, Which Can Lead to Ca2+ Release from the ER
Ca2+ Intracellular Levels Kept Low: Primary Active
Transport of Ca2+ into ER and Out of Cell
-Na+/Ca2+ Antiports in Plasma Membrane
Ca2+ Responses in Animals Muscle Contraction Regulated Secretion Cell Division
- regulated by conc of Ca2+
- phospholipase
G-Protein bg Subunits Can Also Activate Ion Channels
Binding of NT ACh to its GPCR on heart cells results in activation of G protein Gi. Activated By complex directly opens a K+ channel in PM, increasing its permeability to K+ and making mem harder to activate and slowing HR. INactivation of a subunit by hy
Turning Off G-Protein Linked Receptor Signaling Involves GTP Hydrolysis and Formation of Trimeric Complex
A G-Protein is an Example of a Molecular Switch through GTP hydrolysis
- form diff trimeric complexes
- whether active or inactive, mediate effects on target proteins
- when activated a subunit interacts with its target protein, it (in)activates it
- norm
Enzyme Linked Receptors
Primarily involved in:
Cell Growth, Proliferation,
Differentiation and Survival
- can effect diff cells' survival: survive, die, or differentiate
Paracrine or Endocrine Signaling
Signals are Local Mediators or Hormones
Characteristics of Receptors:
-Singl
1. Tyrosine Kinase Linked Receptors
JAKs Activate STATs
to Alter Gene Transcription
- prolactin receptor
- activation of STAT proteins
- when phosphorylated in dimer state, can transverse into nucleus (through nuclear pores)
- involved in upregulation and transcription of genes
Paracrine an
2. Receptor Tyrosine Kinases (RTK)
Assembly of an Intracellular Signaling Complex Allows Several Pathways to be Activated at the Same Time
Activation of an RTK stimulates assembly of intracellular signaling complex - binding of signal molecule to extracellular domain of RTK causes 2 recept
Virtually All Receptor Tyrosine Kinases Activate a Monomeric G-protein RAS Family Member
RTKs activate Ras
An adaptor protein docks on a particular phosphotyrosine on activated receptor. Adaptor recruits a Ras guanine nucleotide exchange factor (Ras-GEF) that stimulates Ras to exchange its bound GDP for GTP
- activated Rs protein can now stim
RAS-GTP Can Activate a
Kinase Phosphorylation Cascade (Pathway)
Ras activates a MAP-kinase signaling molecule
- Ras activates a 3-kinase signaling module that relays the signal - final kinase (MAP kinase) phosphorylates various downstream signaling or effector proteins
RAS activates a Kinase that Activates another Kin
Turning Off RAS Mediated RTK Signaling Pathways: Requires GTP Hydrolysis by Ras and the Activity of Phosphatases
Phosphatases Remove a Phosphate from a Protein: Dephosphorylate
1. signaling by phosphorylation
if have RAS in OFF, to turn ON, need signal to come in- actiate a kinase, phosphorylate to turn on - will release a signal later that cascades down to (in)acti
RTKs activate the PI-3 Kinase- Akt Signaling Pathway
An extracellular survival signal (ex. IGF) activates an RTK, which recruits/activates PI 3-kinase - phosphorylates inositol phospholipid embedded in cytosolic side of PM. Resulting phosphorylated inositol phospholipid then attracts intracellular signaling
Signaling Networks
Convergence, Divergence and Cross Talk Between Signaling Pathways
Both GPCRs and RTKs activate multiple intracellular signaling pathways
- 2 pathways lead from GPCRs through adenylyl cyclase and through phospholipase C, and 3 leading from RTKs through pho
The Role of Nitric Oxide (NO) as a Paracrine Signaling Molecule
synth'd from AA arg and diffuses into neighboring cells - released by endothelial cells (lining and lumen of BVs) in response to NTs secreted by nerve endings - smooth muscle relaxes, blood flows
- dissolved gas- directly regulates activity of specif intr
Adhesion Between Cells and Between Cells and their Environment
I. Cells-Cell Recognition and Adhesion
II. Cell-Cell Junctions
1.Tight Junctions
2. Gap Junctions
3. Adhesive (Anchoring) Junctions
III. The Extracellular Matrix of Animal Cells 1.Matrix Structural Proteins
2. Matrix Polysaccharides
3. Matrix Adhesive Gly
what is role of polysaccharides in ECM?
...
role of glycoproteins in ECM?
...
role of integrin in ECM?
...
Interactions Between Cells & Their Environment
Cells Interact with Other Cells or with Extracellular Material to Form Tissues
Main Types of Tissue of Animals
- Connective, Epithelial, Nervous, Muscular, and Blood
Cell-Cell and Cell-ECM Interactions Mediate Additional Diverse Activities including:
1. C
Epithelial and Connective Tissue
Epithelial Tissue
Loose Connective
Tissue
see fig for parts!
I. Cell-Cell Recognition and Adhesion
� The Ability of Cells to Recognize, Adhere, and Communicate with other Cells is Critical in formation of tissues, organs, and organ systems.
� Cell-Cell Contact Can Occur Transiently
- Dynamically assemble and disassemble adhesions in
response to variety
Major Families of CAMs Transmembrane Proteins Mediating Cell-Cell Adhesion
1. Cadherins
2. CAMs
3. Integrins
4. Selectins
- all exp diff CAMs (plasma membrane receptors)
Cells selectively express Plasma membrane Receptors (CAMs) with Limited Ligand Binding Activity
Adhesive Structure Not Necessarily Static!
- lots of flux to int
Cadherin Mediated Cell Adhesion
Homophilic and Dependent Upon Ca2+
Cadherin Proteins Play an Integral Role in Animal Cell-Cell Adhesion
when cells properly exping E-cadherin, can be used to organize cell
- N-cadherin and E-cadherin
- when Ab added to blastulas to inhibit activity of E-cadherin, causes disassembly - fall apart
II. Cell-Cell Junctions
� Specific Means of Joining Cells in Long Term Association/communication to Form Tissues and Organs
Three Functional Groups:
1.Tight Junctions
2.Gap Junctions
3. Adhesive Junctions
tight junctions
Form Semi-Permeable Barriers
and Preserve Cell Polarity
- monitor intake of diff molecule thru Na/glucose symport
- interaction of diff PMs and sealing of tight junctions
Regulate Paracellular Transport
- how molecules enter into cells or are passed btwn
gap junctions
serve to provide cyto contact btwn adj cells
--Provides Cytoplasmic Contact Between Two Adjacent Cells
-Formed by Integral Membrane protein Connexin- Clusters to form Connexons
-Permeability Can Be Regulated
-Small molecules - second messengers can pass
-
adhesive junctions
actin?
claudin
involved in tight junctions
Adhesive Junctions: Desmosomes
Connect Intermediate Filaments From Cell to Cell
- involved w keratin filaments
- form button point of adhesion
- cadherin - involved in connection of 1 cell to another
- function - to help cells communicate as a unit in a tissue
- resist some stress
Adherens Junctions (Adhesion Belts)
Indirectly Link Actin
Cytoskeleton Of Adjacent Cells
- can bundle next to actin filaments
- add strength - help to anchor proteins of dimers
Adhesion Belts and Epithelial Movement
Creating Specialized Structures
- invagination of cells
- adhesion belt formed along tube
- cadherins involved in space
signal transduction
process of conversion of signals that carry info from one form to another
- begins when receptor on target cell receives incoming extracellular signal and converts it to intracellular signaling molecules that alter cell beahvior
signaling cell
produces extracellular signal molecule detected by target cell
receptors
proteins on target cells that recognize/respond specifically to signal molecule
- primary step in signal transduction -recognizes extracellular signal and makes new intracellular signals in response -- message passed downstream from one INTRACELLULAR SIGN
hormones/ endocrine signaling
extracellular signals sent throughout body by secreting into bloodstream
- cell-cell communication
- produced by endocrine cells
- each regulates diff sets of genes in diff cells - diff responses in diff target cells
paracrine signaling
signal molecules diffuse locally through extracellular fluid, remaining in area of cell that secretes them
- act as LOCAL MEDIATORS on nearby cells
- as in inflammation in infection / cell proliferation
autocrine signaling
cells respond to local mediators they produce
- form of paracrine signaling
- ex: how cancer cells survive/proliferate
neuronal signaling
message to individual target cells through azons - leave axon terminal as NT - diffuses across gap to target cell
effector proteins
direct effect on target cell behavior
extracellular signal molecules - 2 classes
1. cell-surface receptors
- too large/hydrophili to cross PM of target cell- bind to receptors on target cell surface- generate 1+ intracellular signaling molecules in target cell - relay message across membrane
2. intracellular receptors
- small, hydroph
steroid hormones
family of signal molecules that rely on intracellular receptor proteins
- hydrophobic molecules pass through PM of target cell and bind to receptor proteins in cytosol/nucleus
- includes thyroid hormones (thyroxine)
nuclear receptors
cytosolic and nuclear receptors - when activated by hormone binding, act as transcription regulators in nucleus
- in unstimulated cells, inactive
- when hormone binds, undergoes conf change - allows protein to promote/inhibit transcription of target genes
4 intracellular signaling pathway functions
1. relay signal onward and spread it through cell
2. amplify signal received - making it stronger, so few extracellular signal molecules evoke large intracellular response
3. detect signals from more than 1 intracellular signaling pathway and integrate th
feedback regulation
positive: downstream component acts on earlier component to enhance response to initial signal
negative: downstream component inhibits earlier one to diminish response
molecular switch
receipt of signal causes toggle from inactive to active state
- once activated, stimulate other proteins in signaling pathway
- persist in active state until another process switches them off again
- kinases and phosphatases
- phosphorylation cascades - 1
2 main types of kinases in intracellular signaling pathways
1. serine/threonine kinases - phosphorylate proteins on serines/threonines
2. tyrosine kinases- phosphorylate proteins on tyrosines
2 main types of GTP-binding proteins in intracellular signaling pathways
1. trimeric GTP-binding proteins (G proteins) relay messages from GPCRs
2. monomeric GTPases relay signals
- Guanine nucleotide exchange factors (GEFs) switch GTP binding proteins ON by exchanging GDP for GTP
- GTPase-activating proteins (GAPs) turn GTP b
g protein
when extracellular signal molecule binds to GPCR receptor protein undergoes conf change that enables it to activate a g protein on other side of PM
phospholipase C
membrane-bound enzyme - once activated, propagates signal by cleaving lipid molecule - component of PM - an inositol phospholipid (sugar inositol attached to head) in small amts in cytosolic leaflet of membrane lipid bilayer
- regulates effector proteins
IP3
water-soluble sugar phosphate released into cytosol- binds to/opens Ca2+ channels embedded in ER membrane
- Ca2+ stored in ER rushes out into cytosol through these open channels, causing sharp rise in cytosolic conc of free Ca2+ - normally kept low - Ca2+
Diacylglycerol
lipid embedded in plasma membrane after made by phospholipase C - helps recruit/activate Protein Kinase C (PKC) that translocates from cytosol to PM - needs to bind Ca2+ to become active
- once activated, PKC phosphorylates a set of intracellular proteins
adrenaline
originates in adrenal gland
- deriv of AA tyrosine
- increases BP, HR and metabolism
cortisol
originates in adrenal gland
- steroid (deriv of cholesterol)
- affects metabolism of proteins, carbs, and lipids in most tissues
EGF - epidermal growth factor
originates in various cells
- protein
- stimulates epidermal and many other cell types to proliferate
NO - nitric oxide
originates in nerve cells; endothelial cells lining BVs
- dissolved gas
- causes smooth muscle cells to relax; regulates nerve-cell activity
Acetylcholine
originates in nerve terminals
- derivative of choline
- excitatory NT at many nerve-muscle synapses and in central NS
Delta
originates in prospective neurons; various other developing cell types
- transmembrane protein
- inhibits neighboring cells from becoming specialized in same way as the signaling cell
Nicotine
- normal signal = Acetylcholine
- receptor action: stimulates acetylcholine-activated ion-channel-coupled receptors
- effect: constriction of BVs; elevation of BP
Curare
- normal signal = acetylcholine
- receptor action: blocks acetylcholine-activated ion-channel-coupled receptors
- effect: blockage of neuromuscular transmission, resulting in paralysis
3 target tissues of adrenaline
1. heart - increase in HR and force of contraction
2. skeletal muscle- glycogen breakdown
3. fat - fat breakdown
ACTH targets adrenal gland - cortisol secretion
receptor tyrosine kinase (RTK)
receptor with cytoplasmic domain that functions as a tyrosine protein kinase, which phosphorylates particular tyrosines on specific intracellular signalling proteins
- largest class of enzyme-coupled receptors
interaction domain
recognizes specific phosphorylated tyrosines on receptor tails
- others allow intracellular signaling proteins to recognize phosphorylated lipids made on cytosolic side of PM in response to signals
- signaling protein complexes assembled on cytosolic tail
MAP kinase (signaling molecule)
mitogen-activated protein kinase
- 3 protein kinase module
- included in relay system in which Ras initiates a phosphorylation cascade and a series of serine/threonine kinases phosphorylate and activate one another in sequence
- phosphorylated and activat
mitogen
extracellular signal molecule that stimulates cell proliferation
PI 3-kinase
phosphorylates inositol phospholipids in plasma membrane
- these phosphorylated lipids serve as docking sites for intracellular signaling proteins - relocate from cytosol to PM where they activate one another
Akt / PKB
relocated signaling protein
- promotes growth/survival of cell types by inactivating signaling proteins it phosphorylates
- ex: Bad - encourages apoptosis
PI-3-kinase-Akt signaling pathway
stimulates cell growth by indirectly activating a large serine/threonine kinase Tor - stimulates cells to grow by enhancing protein synth and inhibiting degradation - by phosphorylating and inhibiting a protein that keeps Tor shut down
- anticancer drug r