Transcript Cell Signaling: A Molecular View

Cell Signaling: A Molecular View
Shuchismita Dutta, Ph.D.
Developed as part of the RCSB Collaborative Curriculum Development Program 2016
Learning Objectives
• Introduction to Cell Communication
• Cell Signaling Pathways
Developed as part of the RCSB Collaborative Curriculum Development Program 2016
Learning Objectives
• Introduction to Cell Communication
• Cell Signaling Pathways
Developed as part of the RCSB Collaborative Curriculum Development Program 2016
Who Communicates? Why?
• Unicellular organisms
Normal cells
– To sense environment
• Is there enough food/light?
• Are there toxins in the vicinity?
+ mating factor
• Cells in multicellular organisms
– To function cooperatively with neighboring and
distant cells of the organism
• Initiate protein synthesis only when enough glucose is
present
http://www.ncbi.nlm.nih.gov/books/NBK26813/
Developed as part of the RCSB Collaborative Curriculum Development Program 2016
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
http://www.ncbi.nlm.nih.gov/books/NBK26813/
Developed as part of the RCSB Collaborative Curriculum Development Program 2016
Types of Cell Communication-2
Endocrine
• 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
Exocrine
• 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
http://www.ncbi.nlm.nih.gov/books/NBK26813/
Developed as part of the RCSB Collaborative Curriculum Development Program 2016
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
http://www.ncbi.nlm.nih.gov/books/NBK26813/
Developed as part of the RCSB Collaborative Curriculum Development Program 2016
Learning Objectives
• Introduction to Cell Communication
• Cell Signaling Pathways
Developed as part of the RCSB Collaborative Curriculum Development Program 2016
Cell Signaling Steps
1. Reception
2. Transduction
3. Response
Adapted from http://www.ncbi.nlm.nih.gov/books/NBK21059/figure/A2741/
Developed as part of the RCSB Collaborative Curriculum Development Program 2016
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)
http://www.ncbi.nlm.nih.gov/books/NBK21059/figure/A2741/
Developed as part of the RCSB Collaborative Curriculum Development Program 2016
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)
http://www.ncbi.nlm.nih.gov/books/NBK21059/figure/A2741/
Developed as part of the RCSB Collaborative Curriculum Development Program 2016
Examples of Cell Surface Receptors
Ion channel linked
G-Protein linked
Enzyme linked
Ion
channel
Kinase
(enzyme)
domain
G-Protein binding
Acetylcholine receptor
Serotonin receptor
Acetylcholine (red)
Serotonin (blue)
In all these figures the membrane is schematically shown in gray
Insulin receptor
Insulin (red)
Developed as part of the RCSB Collaborative Curriculum Development Program 2016
Example of Nuclear Receptor
• Estrogen binds to
receptors in nucleus 
affects key genes in
development
• Ligand binding domain
and DNA binding
domains linked by
connectors
DNA
Binding
Domain
DNA
Connector,
not shown
Ligand
Binding
Domain
Estrogen
Estrogen Receptor
Developed as part of the RCSB Collaborative Curriculum Development Program 2016
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
http://www.ncbi.nlm.nih.gov/books/NBK21059/figure/A2741/
Developed as part of the RCSB Collaborative Curriculum Development Program 2016
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
Active conformation
Inactive conformation
Developed as part of the RCSB Collaborative Curriculum Development Program 2016
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
Signal amplification
Inactive conformation
Active conformation
Developed as part of the RCSB Collaborative Curriculum Development Program 2016
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
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
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