Sustaining Proliferative Signaling and Evading Growth Suppressors Oct 19, 2017

Hallmarks of Cancer, 2011

Signal Transduction Proteins may Relay the signal to the next protein Scaffold proteins bring components together to be more efficient

Signal Transduction The signal may be transduced into a more suitable form Amplification – many copies of the signal may be produced Signaling cascade – signal transduction with multiple amplification steps

Signal Transduction Signals may come from more than one pathway and need to be integrated The signals may spread from one pathway to another (aka cross-talk)

Signal Transduction The signaling proteins may be anchored to a particular location where they are needed The activity of other signaling proteins may be modulated thereby regulating the strength of the final signal

Intracellular Signaling Switches Molecular Switches

Intracellular Signaling Switches Phosphorylation cascades 2 types: Serine/Threonine kinases Tyrosine kinases

Intracellular Signaling Switches 2 forms of GTPases: Trimeric GTP-binding proteins (G-Proteins) Monomeric GTP-binding proteins (Monomeric GTPases)

Monomeric GTPases GAP – GTPase-activating protein GEF – Guanine nucleotide exchange factor

Signal Integration 2 different signals are needed to create the downstream signal Coincidence detector

Other Signaling Methods 1. Other Molecular switches include binding of cAMP or Ca+2 2. Other covalent modification such as ubiquitination 3. Some signaling molecules don’t have direct enzymatic activity but just bind with other proteins and aid them in further interaction

Scaffold Proteins A single Extracellular signal binding to 1 receptor often activates multiple parallel signaling pathways and affect multiple cell behaviors How do you avoid cross-talk? Scaffold Proteins Bind groups of interacting signaling proteins into signaling complexes

Assembly on an Activated Receptor Phosphorylation of cytoplasmic receptor tail allows binding of signaling proteins Advantage: Rapid assembly and disassembly

Phospholipid Signaling

-Phosphatidyl inositol is found in the cytosolic monolayer

Interaction Domains Interaction domains on signaling proteins allow them to bind to other proteins in the pathway to create a signaling pathway Each domain binds to a different structural motif -short peptides -covalent modification -another protein domain

Domain Shuffling Allows for new protein-protein interactions to evolve New gene responsible for a new protein with a new function

Types of Interaction Domains SH2 – Src homology 2 domain -binds to phosphorylated tyrosines SH3 – Src homology 3 domain -Binds to short proline-rich amino acid sequence PH – Pleckstrin homology -Binds to the charged head groups of specific phospholipids Adaptors – contain 2 or more interaction domains and serve just to bring the other proteins together

Insulin Receptor Complex

Lipid Rafts Help to cluster receptors and intracellular signaling proteins

Receptor Concentration

Methods of Receptor Concentration

Types of Signaling Responses Graded Switch-like

Progesterone Signaling in Frog Oocytes

Progesterone Signaling in Frog Oocytes Two possible mechanisms!!! Oocytes need to be tested individually Result: All or None (C)

Effector Molecule Effects Graded responses can also be very steep Depends on the Strength of the signal Number of Effector molecules (signals) Example: PKA (cAMP-dependent protein kinase) -4 cAMP molecules Cooperative response

Effector Molecule Effects Graded responses can steepened Also occurs if the Signaling molecule both: Activates an enzyme Inhibits another enzyme Example: Adrenaline, cAMP increases are a result to receptor binding Promotes glycogen breakdown Inhibits glycogen synthesis Cooperative response

Feedback Loops Positive Feedback – the output stimulates its own production Negative Feedback – the output inhibits its own production Timing – Vary Signaling – the feedback could involve either intracellular or extracellular signals

Positive Feedback -Necessary for All-or-None responses -Once the feedback molecule reaches a critical concentration, a new level of activity/production occurs

Positive Feedback Once a system has reach a high level of activation, the condition can persist even in the absence of the signal A transient signal can produce a strong enough positive feedback to continue its effect for the life of the cell Seen in cell fate/development

Negative Feedback Activating a phosphatase to inactivate the Enzyme The length of the delay of the negative feedback can affect the activity of the enzyme differently -a short delay causes a strong brief response -a long delay causes oscillations while the signal is present

Desensitization A decrease in the cell’s response to a given level of stimulus over a prolonged exposure

Faculty Candidates Monday, Oct 23 11am-12pm Teaching Demonstration SSN381 2:45-3:30pm Meet with Students Bio Office 4-5pm Research Seminar Mer112 Friday, Oct 27 After lunch Meet with Students Bio Office Monday, Oct 30