1. Cell Signaling: A Molecular View
Shuchismita Dutta, Ph.D.
Developed as part of the RCSB Collaborative Curriculum Development Program 2016

2. Introduction to Cell Communication Cell Signaling Pathways
Learning Objectives
Introduction to Cell Communication
Cell Signaling Pathways
Developed as part of the RCSB Collaborative Curriculum Development Program 2016

3. Introduction to Cell Communication Cell Signaling Pathways
Learning Objectives
Introduction to Cell Communication
Cell Signaling Pathways
Developed as part of the RCSB Collaborative Curriculum Development Program 2016

4. Unicellular organisms
Who Communicates? Why?
Unicellular organisms
To sense environment
Is there enough food/light?
Are there toxins in the vicinity?
Cells in multicellular organisms
To function cooperatively with neighboring and distant cells of the organism
Initiate protein synthesis only when enough glucose is present
Normal cells
+ mating factor
Developed as part of the RCSB Collaborative Curriculum Development Program 2016

5. Types of Cell Communication-1
Autocrine
Regulate self or group of similar cells
e.g., Signaling of some interleukins e.g. IL-6
Growth signaling in many types of cancer cells
Gap Junctions
Direct contact between adjacent cell cytoplasm
Transport of ions and small molecules between cells (e.g., between adjacent neurons)
Paracrine
Signal induces changes in neighboring cells
e.g., Signaling by Fibroblast growth factors
Developed as part of the RCSB Collaborative Curriculum Development Program 2016

6. Types of Cell Communication-2
Endocrine
Exocrine
Secretion of hormones - directly into blood for transport to target cells
Action seen in target cells far from the source
Action is prolonged
Insulin - secreted by pancreas, acts on liver, muscle, and fat cells
Secretion of enzymes and/or other fluids e.g., sweat, saliva via specific ducts
Action close to site of secretion
Activity short-term
Pancreatic digestive enzymes - trypsin, chymotrypsin, elastase, carboxypeptidase, lipase, amylase
Compare endocrine and exocrine communications:
Developed as part of the RCSB Collaborative Curriculum Development Program 2016

7. Properties of Cell Signals
Cells are programmed to respond to signals (and combinations of signals) in specific ways
Different cells may respond to the same signal in different ways
Developed as part of the RCSB Collaborative Curriculum Development Program 2016

8. Introduction to Cell Communication Cell Signaling Pathways
Learning Objectives
Introduction to Cell Communication
Cell Signaling Pathways
Developed as part of the RCSB Collaborative Curriculum Development Program 2016

9. Cell Signaling Steps 1. Reception 2. Transduction 3. Response
Adapted from
Developed as part of the RCSB Collaborative Curriculum Development Program 2016

10. Receptor specifically binds signal molecule (sometimes called ligand)
Step 1: Reception
Receptor specifically binds signal molecule (sometimes called ligand)
Cell surface receptors
Embedded in plasma membrane
Bind water-soluble ligands
Intracellular receptors
Present in cytoplasm or nucleus
Binds small and hydrophobic ligands (that can pass through the cell membrane)
Developed as part of the RCSB Collaborative Curriculum Development Program 2016

11. Types of Cell-Surface Receptors
Linked to ion channel
e.g., ligand gated Ca2+ channels
Linked to G-Protein
e.g., Glucagon receptor
Linked to Enzymes
e.g., Insulin receptor (Tyr Kinase is part of the receptor)
Developed as part of the RCSB Collaborative Curriculum Development Program 2016

12. Examples of Cell Surface Receptors
Ion channel linked
G-Protein linked
Enzyme linked
Ion channel
Learn more about:
Acetylcholine Receptors at
Serotonin Receptors at
Insulin Receptors at
Kinase (enzyme) domain
G-Protein binding
Acetylcholine receptor
Acetylcholine (red)
Serotonin receptor
Serotonin (blue)
Insulin receptor
Insulin (red)
In all these figures the membrane is schematically shown in gray
Developed as part of the RCSB Collaborative Curriculum Development Program 2016

13. Example of Nuclear Receptor
DNA Binding Domain
Estrogen binds to receptors in nucleus  affects key genes in development
Ligand binding domain and DNA binding domains linked by connectors
DNA
Connector, not shown
Ligand Binding Domain
Estrogen
Learn more about Estrogen Receptors at
Estrogen Receptor
Developed as part of the RCSB Collaborative Curriculum Development Program 2016

14. Step 2: Signal Transduction
Relay signals from receptors to target(s)
Second messenger: small molecules in cytoplasm
Messenger molecules: proteins relaying message
Many are molecular switches – turn on and off
Types of messenger protein:
Relay protein or messenger
Adaptor proteins
Amplifier
Transducer
Integrator
Developed as part of the RCSB Collaborative Curriculum Development Program 2016

15. Phosphorylation Controlled Activation
Src Tyrosine Kinase
Inactive:
Phospho-Tyr binds to SH2 domain
Enzyme active site blocked
Active:
Dephosphorylation of Tyr releases tail from SH2 domain
Enzyme active site open for substrate binding
Learn more about Src Tyrosine Kinase at
Active conformation
Inactive conformation
Developed as part of the RCSB Collaborative Curriculum Development Program 2016

16. GTP Binding Controlled Activation
G-Protein Coupled Adrenaline Receptor
Inactive
Composed of a, b, g trimer
GDP bound
Active
GTP binds
The b, and g subunits separate
The a subunit binds to adenylate cyclase  produce cAMP
Learn more about G Proteins at
Signal amplification
Inactive conformation
Active conformation
Developed as part of the RCSB Collaborative Curriculum Development Program 2016

17. Regulation of cytoplasmic activities
Step 3: Response
Regulation of cytoplasmic activities
Rearrangement of cytoskeleton
Movement of vesicles to cell surface
Release of stored hormones, messengers etc.
Translocate specific receptors/channels to cell surface
Activation or inhibition of enzyme(s)
Regulation of nuclear activities
Gene regulation – activation or inhibition
Transcription  cell proliferation/differentiation
Developed as part of the RCSB Collaborative Curriculum Development Program 2016

18. Feedback Regulation All cell signals must be attenuated
Feedback mechanisms at all the steps may regulate the response
Surface receptors may be internalized
Signal transducers may be removed/modified
e.g., Ca2+ ions sequestered or PO4 proteins de-PO4
Response may produce new proteins that block signaling
Developed as part of the RCSB Collaborative Curriculum Development Program 2016

19. Introduction to Cell Communication Cell Signaling Pathways
Summary
Introduction to Cell Communication
Types and Properties
Cell Signaling Pathways
Reception, Signal Transduction and Response
Developed as part of the RCSB Collaborative Curriculum Development Program 2016