IBS 8102 Cell, Molecular, and Developmental Biology Cell Cell Communication January 29, 2008
Communicate What? Why do cells communicate? To govern or modify each other for the benefit of the organism differentiate multiply perform specialized physiology; e.g. secrete contract die (i.e. undergo apoptosis)
Mechanism I. Signaling molecules intercellular intracellular A. Long distance neurotransmitters hormones B. Short distance paracrine factors juxtacrine factors autocrine factors ECM components III. Intracellular signaling proteins (Signal Transduction components) distribute external signals often enzymatic phosphatases kinases GTP binding/hydrolysis II. Cellular interaction A. Diffusion lipophilic molecules may diffuse through membrane NO steroid hormones B. Ion channels C. Gap junctions D. Receptors membrane bound cytoplasmic cytosolic nuclear IV. Target proteins transcriptional regulators ion channels metabolic pathways cytoskeletal components etc.
Intrercellular Signaling Major Paracrine Factor Families Fibroblast growth factor (FGF) Hedgehog family Wingless family (Wnt) TGF β superfamily (TGF = transforming growth factor) TGF β family Activin family Bone morphogenic proteins (BMPs) Vg1 family
Signal Transduction Extracellular signals are transduced to the cytoplasm at the cell membrane external signal is transmitted into the interior of the cell Signal transduction cascades most intercellular and intracellular signals are part of larger set of pathways activated products or intermediates trigger other pathways e.g. receptor tyrosine kinase (RTK) (kinase = protein phosphorylating enzyme)
Signal Transduction Model e.g. Receptor Tyrosine Kinase (RTK) receptor spans membrane ligand binding = conformational change = hormone or paracrine factor autophosphorylation intracellular signal
RTK Pathway FGF (Generic) 1. Ligand binding 2. RTK dimerized 3. RTK autophosphorylation 4. Adaptor protein binding 5. GNRP binding (guanine NT releasing protein) 6. GNRP activates Ras (G protein) 7. Ras GDP Ras GTP 8. [GAP recycles Ras] 9. Ras activates Raf (protein kinase C;PKC) 10. Raf phosphorylates MEK (a kinase) 11. MEK phosphorylates ERK (a kinase) 12. ERK phosphorylates transcription factor 13. Transcription modulation
Proto Oncogenes Proto oncogenes (onco = cancer) Proto oncogenes are active during development repressed/silenced in adult Mutations (e.g. constitutive activation) = oncogene many cancers have mutated proto oncogenes e.g. mutated Ras found in 20 30% of all tumors
RTK Pathway MITF MITF microphthalmia transcription factor Stem cell factor (paracrine factor) stimulates genes needed for melanocyte production.
JAK STAT Pathway JAK Janus kinase non receptor tyrosine kinase STAT Signal Transducers and Activators of Transcription transcription factor Pathway activators: prolactin cytokines, growth hormones; cell proliferation differentiation apoptosis NOTE STATs can be activated independently of JAKs RTK; e.g. EGF receptor non receptor tyrosine kinases; e.g. c src
Hedgehog Pathway Generic Drosophila Mammalian Ci homolog Gli zinc finger TF
Canonical Wnt pathway Wnt Pathways Drosophila Wingless mouse Integration Wnt GSK 3 Glycogen synthase kinase 3 prevents β catenin dissociation from APC APC adenomatosis polyposis coli (tumor suppressor) targets β catenin for degradation Wnt binds to Frizzled receptor family activates Disheveled Disheveled blocks GSK 3 β catenin released from APC enters nucleus associates with LEF/TCF TFs NOTE actual picture more complex than this; many other possible participants; e.g. at surface co receptors, etc. cytoplasmic G protein, other actors
Planar cell polarity pathway Wnt Pathways Ca 2+ pathway tether (inactive) phospholipase C IP3 diacylglycerol a. Rho: GTPase b. Rac: GTPase Rhoassociated kinase Jun kinase phosphatase cell morphology, movement, division Ca 2+ dependent gene expression
TGF β superfamily ligands TGF βs BMPs Activins Dpp Inhibin Nodal Vg1 etc. SMAD Pathway C. elegans Sma Drosophila Mad Smad R Smad co Smad
Apoptosis Apoptosis programmed cell death Developmental: embryonic neural growth embryonic brain produces 3X neurons found at birth hand and foot webbing between digits teeth middle ear space vaginal opening male mammary tissue frog tails (at metamorphosis) Adult: most cells and tissues
Apoptosis Mechanism Apoptosis triggered by developmental and metabolic signals homologs Often pre programmed: inhibited until signal received Signaling pathways: Developmental: BMP JAK STAT Hedgehog Adult: TNFR (Tumor necrosis factor receptor) TNF FAS Mechanism: CEDs, Caspases proteases
Notch Pathway Juxtacrine signaling: Proteins from the inducing cell interact with receptors from adjacent responding cells without diffusing from the cell producing them. e.g. Notch/Delta, Ephrin/EphR, EGF/EGFR, IL 15/IL 15Rα, etc. Delta protein bind Notch protease cleaves both outer and inner Notch portions outer portion remains with ligand endocytosed into ligand expressing cell may act as signal (Serrate) (Jagged) inner portion moves to nucleus displaces repressor recruits p300 HAT activates transcription
Extracellular Matrix ECM macromolecules secreted by cells into their immediate environment form a region of non cellular material in the intersticies between the cells proteoglycans: e.g. heparan sulfate, chondroitin sulfate, keratan sulfate polysaccharides; e.g. hyaluronic acid proteins: e.g. collagen, fibronectin, elastin, laminin ECM Function cell adhesion, migration, formation of epithelial sheets and tubes intracellular signaling
ECM Mediated Cell Adhesion Different cells have different cadherins. Different cadherins have different affinities for each other. Thus, cell types can segregate themselves based on membrane components. actin microfilament system = anchoring and movement NOTE Ca 2+ dependent binding: Ca 2+ can control both strength and reversibility of binding
Extracellular Matrix Signals
ECM Signal Transduction ECM components; e.g. fibronectin Trans membrane receptor; e.g. integrin binds to ECM RGD sequence binds to cytoskeletal components regulation inside and out integrin subunit α Ca 2+ Signal transduction: cytoskeleton talin, vinculin, paxillin, α actinin can regulate kinase activity Src family focal adhesion kinase (FAK) kinase regulation
Cross Talk Signal transduction is often not a linear event; e.g. cascades multiple signals required multiple products required also: inhibitory signals promiscuous signals/receptors Cross talk provides opportunities for emergent properties; e.g. hypersensitivity stability bistability
Maintaining Differentiation 2 2) Synthesized proteins act to stabilize chromatin to keep gene accessible.
Maintaining Differentiation Autocrine Signaling 3) Autocrine signaling: same cell makes both the signaling molecule and receptor.
Maintaining Differentiation Community Effect 4) Interaction with neighboring cells such that one stimulates differentiation of the other.