SC430 Molecular Cell Biology

• Welcome to Unit 7 Seminar with Dr Hall-Pogar

• Tonight we will discuss – Diseases that result from errors in cell signaling

pathways and available treatments– I will be available at AIM:KaplanHallPogar

before and throughout the seminar if you have any questions or issues.

• We will begin promptly at 8:00pmEST

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Unit Review

• DB

• Quiz

• Project– Due this Unit 7 – Part I: Protein Synthesis– Part II: Protein Mutations

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Cell to Cell Communication

• Juxtacrine signaling - with each other via direct contact

• Paracrine signaling - over short distances • Endocrine signaling - over large distances• Some cell-to-cell communication requires

direct cell-cell contact cells form gap junctions

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Cell signaling: responding to the outside world

•Cells interact with their environment by interpreting extracellular signals via proteins that span their plasma membrane called receptors

•Receptors are comprised of extracellular and intracellular domains

•The extracellular domain relays information about the outside world to the intracellular domain

•The intracellular domain then interacts with other intracellular signaling proteins

•These intracellular signaling proteins further relay the message to one or more effector proteins

•Effector proteins mediate the appropriate response

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Receiving the Signal: G-protein Coupled Receptors (GPCRs)

•GPCRs are an important and ubiquitous class of eukaryotic receptors (>700 in humans)

•The intracellular domain is coupled to a heterotrimeric G-protein

•When the G subunit is bound to GDP it is “OFF”; when it is bound to GTP it is “ON”

•When the extracellular domain binds to the signal molecule, it causes a conformational change relayed through the transmembrane spans to the intracellular domain

•The conformational change relayed to the intracellular domain causes the G subunit to release GDP and bind to GTP thereby activating both the G and G/G subunits

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What are G-proteins?• G proteins bind GTP: guanosine triphosphate. Control and amplify

intracellular signaling pathways

Exist in two states 1) bound GTP: active

2) bound GDP: inactive

Fig. 15.1

Examples of GTPase proteinsRas, Cdc-42

(hormone, GF, drug)

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GTPases and disease.

• Damage to these small GTPase switches can have catastrophic consequences for the cell and the organism.

• Several small GTPases of the Rac/Rho subfamily are direct targets for clostridial cytotoxins.

• Ras proteins are mutated to a constitutively-active (GTP-bound) form in approximately 20% of human cancers.

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Insulin Signal Transduction CascadesInsulin Promotes Cell growth, Glucose uptake

and storage• Insulin Receptors (IR) bind 2 insulin peptide with 2

α chains– β chains (auto-)phosphorylate each other– P- β subunits now active tyrosine kinases

• Active RTK initiates a signal transduction cascade– RTK phosphorylates Insulin Receptor Substrate-1

(IRS-1)• Adaptor proteins Grb2 and Sos bind to P-Tyr-

IRS-1 via SH2 domain– Sos activates Ras GTPase

• Ras.GTP activatesProtein Kinase Cascade– Ras activates Raf-1 kinase (MAPKKK)– Raf-1 kinase activates MEK kinase (MAPKK)– MEK kinase activates ERK kinase (MAPKinase)– ERK kinase activates Elk1 transcriptional

activator

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Disease caused by

• Nature of these defects and how they are induced varies enormously– Examples include pathogenic organisms and viruses

(Cholera, peptic ulcers, Chlamydial diseases)– Mutations– Environmental causes– Remodeling of signal pathways

• Redundancy built into cell signaling mechanisms offers opportunities for discovering new ways of correcting many disease states

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are needed to see this picture.

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Treatment Options

• Small molecule inhibitors

• Antibodies or receptors

• Replacement signal molecules

• microRNA