Cell Signaling 2007

Cells sense and send information (signals) Cells communicate with each other Cells must sense and respond to changes in the environment The signal can come from inside the cell, from another cell, or from the environment. ©2004 Lee Bardwell Cell Signaling

Generic Signaling Pathway Signal Receptor (sensor) Transduction Cascade Output Something happens outside inside (cytosol) ©2002 Lee Bardwell

Something happens Responses to cell signaling Gene expression is altered at the level of transcription, RNA processing or translation Enzyme activities are altered Protein-protein interactions are induced or inhibited The localization of certain proteins and other stuff is altered biochemically ©2002 Lee Bardwell

Something happens Responses to cell signaling The Cell… –divides or stops dividing –differentiates –commits suicide or kills something –moves somewhere or stops moving –alters its metabolism –passes on the signal Physiologically ©2002 Lee Bardwell

What can be a signal? - almost anything Peptides - insulin, glucagon... Proteins Amino acid derivatives - epinephrine, histamine Other small biomolecules - ATP Steroids, prostaglandins Gases - Nitric Oxide (NO) Photons Damaged DNA Odorants, tastants ©2002 Lee Bardwell

Steroid Hormone Signaling Pathway Signal (steroid) Receptor (txn factor)

Steroid Hormone Signaling Pathway Output ∆ gene expression ∆ cell physiology

Signaling cascades have many steps Past: Enumerate components Now: Modules Circuits/ Design Logic Cross-talk Specificity

Adrenaline signaling Signal: Adrenaline (epinephrine) –Secreted by adrenal gland Receptor:  -adrenergic receptor Response: –Breakdown of glycogen to glucose to provide energy for “fight-or-flight”

Insulin signaling Signal: insulin –Secreted by  cells of pancreas Receptor: a receptor kinase Response: –Sugar is taken up from bloodstream into cells Diabetes - type 1, type 2

Growth factor signaling

The growth of multicellular organisms is regulated by more than just nutrient availability NUTRIENTS unicellular eukaryote multicellular eukaryote a edigner

Cells in multicellular eukaryotes require permission signals from growth factors NUTRIENTS a edigner

Disregulation of growth factor signal transduction leads to cancer NUTRIENTS cellular transformation NUTRIENTS

Some growth factors EGF - epidermal growth factor FGF - fibroblast growth factor NGF - nerve growth factor PDGF - platelet-derived growth factor Insulin-like GF All of these bind to a class of receptors known as “Receptor Kinases”

Receptors with enzymatic activity

Protein kinases and phosphatases - Add/remove phosphates to/from proteins - Involved in all signaling from cell surface recetors, and in most other signaling too ©2002 Lee Bardwell

Protein Kinase Reaction Kinase Substrate PPP P ATP

PP P Protein Kinase Reaction Phosphorylation of protein substrates Product

Phosphorylation can flip a protein from “active” to “inactive” or vis-versa ATP ADP

RAF MEK MAPK TXY MEK PP PP PP SP TP The Mitogen-Activated Protein Kinase (MAPK) Cascade

How do protein kinases recognize their protein substrates ? Specificity in MAPK Signalling

Protein Kinase Reaction Kinase Substrate PPP P ATP

PP P Protein Kinase Reaction Phosphorylation of protein substrates Product

Active site - target peptide interaction is not enough for specificity Kinase Substrate

Tethering function: Grewal et al (2006) Cell. Signal. 18:123

Bardwell Lab Lee Bardwell Jane Bardwell Kandarp Shah Lamar Blackwell Tom Whisenant Jeff Rogers Pascal Krotee