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

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

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

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 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 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: 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

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

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

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) 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 Learn more about: Acetylcholine Receptors at http://pdb101.rcsb.org/motm/71 Serotonin Receptors at http://pdb101.rcsb.org/motm/164 Insulin Receptors at http://pdb101.rcsb.org/motm/182 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

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 http://pdb101.rcsb.org/motm/45 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 Learn more about Src Tyrosine Kinase at http://pdb101.rcsb.org/motm/43 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 Learn more about G Proteins at http://pdb101.rcsb.org/motm/58 Signal amplification Inactive conformation Active conformation Developed as part of the RCSB Collaborative Curriculum Development Program 2016

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

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

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