Cell Communication Peter Takizawa peter.takizawa@yale.edu
What we'll talk about... • General principles of signaling • Signaling through steroids and ion channels • Signal transduction pathways • Signaling through G-protein coupled receptors • Signaling through tyrosine kinase receptors
Cells communicate by and respond to messages. Language Response GPSCY, Saturday night? Nah, gotta study the TCA cycle. Detection
Small molecules are the language of cell communication. Amino acids and derivatives Proteins Bind membrane Peptides receptor Di ff use across Gases cell membrane Steroids
The same signaling molecule can evoke different responses. Skeletal muscle: stimulate contraction Acetylcholine Cardiac muscle: reduce contraction
One molecule can elicit multiple cellular changes to produce an integrated response. Muscle: dilate Heart: increase blood vessels contraction Epinephrine Skin: constrict Liver: activate blood vessels glycolysis
Cells generate fast and transient or slow and long- term responses to signaling molecules. Alter protein Slow Fast activity (mins to hours) (sec to mins) New protein synthesis Alter biochemical pathways Alter cell behavior
Types of Cell Communication
Paracrine signaling involves communication between neighboring cells. Degrade Extracellular Matrix Control di ff usion
Endocrine signaling involves communication between cells in different regions of the body. Bind receptor Release Exit hormone capillaries Enter capillaries Travel through blood vessel
Cells can communicate through direct or close contacts. Interaction between integral membrane proteins Cell adhesion creates intimate contact
Endocrine and cell-contact signaling require ligand- receptor binding of different strengths. High affinity interaction Low affinity interaction High concentration of neurotransmitter Low concentration of hormones
Examples of Signaling Pathways
Steroids and small hydrophobic molecules diffuse across plasma membrane. Steroid di ff use across cell membrane Binds receptor or… Receptor releases chaperone …di ff uses into nucleus Receptor enters to bind receptor nucleus Receptor activates transcription
Steroids trigger expression of primary and secondary response genes. Steroid Steroid receptor Proteins that alter biochemical pathways Secondary Primary response response gene gene Transcription factor activates secondary response genes Transcription factor inactivates primary response genes
Ligand-gated ion channels open upon binding ligand. Closed when Open when not bound to bound to ligand ligand Outside Ligand Cytosol
Signal Transduction Pathways
Receptors bind specific signaling molecules and activate cellular events. Receptor binds specific ligand Outside Cytosol Ligand-binding triggers conformational change Activate signaling pathway
GTP-binding proteins function as switches to indicate receptor activation. Receptor-ligand Guanine nucleotide exchange factor GTPase activating protein Downstream pathway
Kinases modulate activity of proteins during signaling reactions. Receptor-ligand Kinase Phosphatase Downstream pathway
Several proteins relay binding state of receptor to cell machinery. Signal transduction Similar between cells pathway Differ between cells Cell B: Cell A: Cell C: Protein Metabolism Morphology expression
Secondary messengers amplify concentration of signaling molecules by producing Ligand = 10 -10 M Signaling pathway Secondary messenger = 10 -6 M Alter biochemical pathway
Cells attenuate signaling reactions to limit amount and time of cellular response. Downstream pathway
Feedback
Negative feedback attenuated signals but also produces patterns of responses. Signal from receptor Phosphorylation activates enzyme Active enzyme turns Phosphatase on a phosphatase inactivates enzyme No No feedback feedback Enzyme Activity Negative Negative feedback feedback Negative Negative feedback feedback
Feedback loops regulate the strength and frequency of signals. Active enzyme Signal from receptor increases its phosphorylation Phosphorylation activates enzyme No feedback Enzyme Activity Positive feedback
Types of Signal Transduction Pathways
G-protein coupled receptors transmit signals through heterotrimeric GTP-binding proteins. Bind ligand β γ α Guanine nucleotide exchange factor γ γ β β α α Heterotrimeric GTP- Downstream Downstream binding protein pathway pathway
G α s subunits activate adenylyl cyclase which convert ATP to cAMP . Adenylyl cyclase G α s Stimulatory G α i Inhibitory ATP cAMP
cAMP activates protein kinase A that has several downstream targets. cAMP Regulatory subunit Protein Kinase A, inactive state Active kinase Catalytic subunit
Phosphodiesterase reduces cAMP levels to limit signaling reactions. Adenylyl cyclase Phosphodiesterase ATP cAMP 5’-AMP
Adenylyl cyclase functions as GTPase-activating protein for G alpha subunits. Adenylyl cyclase G α s G α s ATP cAMP
Phosphatidylinositols are secondary messengers for G-protein coupled receptor pathways. PI kinase PI kinase Phophatidylinositol (PI) PI 4-phosphate [PI(4)P] PI 4,5-phosphate [PI(4,5)P2]
G α s activates phospholipases to generate two new signaling molecules. G α s Phospholipase C Diacylglcerol (DAG) PI 4,5-phosphate [PI(4,5)P2] Inositol-1,4,5 triphosphate (IP3)
IP 3 opens calcium channels in ER and DAG activates protein kinase C. Diacylglcerol (DAG) Protein kinase C PI 4,5-phosphate [PI(4,5)P2] Downstream pathway Inositol-1,4,5 triphosphate (IP3) IP3 Receptor Calcium
Receptor Tyrosine Kinases
Ligand facilities dimerization of receptor tyrosine kinases faciliating cross-phosphorylation. Ligand Outside Cytosol Dimerization leads to Receptor tyrosine kinases cross-phosphorylation
Phosphorylated cytoplasmic domains recruit downstream signaling proteins. Ligand PI kinase GTPase activating protein Phospholipase C Receptor tyrosine kinase
Phosphatidylinositols recruit signaling proteins to the cell membrane which facilitates their activation. PI(4,5)P 2 PI(3,4,5)P 3 Active PI3 kinase Phosphorylation Receptor Inactive tyrosine kinases PDK AKT
Receptor tyrosine kinases recruit proteins to activate Ras which activates a MAP kinase cascade. Ras MAP kinase kinase kinase MAP kinase kinase Guanine nucleotide exchange factor Adaptor protein Receptor MAP kinase tyrosine kinases Biochemical Pathways
Inactivating Receptors
Masking proteins limit the ability receptors to activate downstream components. Active receptor Masking protein Downstream pathway Kinase Downstream pathway inactive
Multivesicular bodies process receptors for degradation in lysosomes. Active receptor Endocytic vesicle Multivesicular body Lysosome
Integrated signaling pathways
Generating a cellular response requires combinations of signaling molecules. Survive Divide Di ff erentiate Apoptosis
Crosstalk between signaling proteins generates nuanced responses.
Take home points... • Signal transduction starts with receptors binding ligand at the cell membrane. • Heterotrimeric G-proteins activate adenylate cyclase and phospholipase C to trigger increase in cytosolic calcium. • Receptor tyrosine kinases recruit proteins to cell membrane and often trigger MAP-kinase pathways. • Cells utilize several mechanisms to turn o ff signals. • Cells integrate signaling pathways stimulated by di ff erent ligand.
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