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Chapter 6- Cell-cell More definitions communication _________-interaction between two or more distinct cells or tissues _________- the cell of tissue producing the signal __________- the cell or tissue being induced _________ the ability to respond to a given inducer Example- Pax6 is required for optic vesicle to respond to an inducer, but Pax6 is not the inducer Hence, Pax6 makes cells _____________ Fig. 6.2 Lacking nose and eyes Wild-type Pax6 null 1. Instructive vs permissive interactions _____________ interaction-Tissue A requires tissue B to respond in a certain way (analogy to a book _______________) ____________ interaction-Tissue A does not require tissue B to respond in a certain way, but only needs to be in a certain environment (analogy to a book ______________) Epithelial-mesenchymal interactions • __________- sheets of cells from any germ layer • ____________- unconnected cells (from mesoderm or neural crest) Mesenchyme • All organs have both of these cell types Wing _______ specificity Thigh Epithelialmesenchymal Foot interactions ________ specificity Wing epithelium Fig. 6.7 Thus, mesenchyme __________ epithelium Epithelial-mesenchymal interactions Newt with tadpole suckers Regional specificity Epithelialmesenchyma l interactions _______ specificity Thus, mesenchyme dictates _______ type, but epithelium dictates ____ of the organ Frog gastrula Newt gastrula Newt gastrula Frog gastrula Frog with newt “balancers” Paracrine factors __________factors- diffusible molecules that can travel small distances to signal a neighboring cell __________signaling- cell-cell interactions by direct contact Example of _________ signaling Fibroblast growth factor (FGF) – binds FGF receptors (FGFRs) These are receptor tyrosine kinases FGF (________) FGFR (______) __________________ yields activation and subsequent phosphorylation of a second protein Other well-known paracrine factors • _________ family- (3 in vertebrates)-create boundaries, induce development • _____ family- (15 in vertebrates)- limb polarity, muscle development • _________ superfamily (>30 members)bone, kidney, neuronal , etc. differentiation BLA512 1/5/98 update Cell surface receptor pathways Enzyme-linked Ion channel-linked G-protein-linked No details shown PDGF, EGF, IFa,b,and g, IL-2 ,IL-3, IL-4, IL-6 TNFa TGF-b PLCg Grb2 Jak G proteins Gs Golf Gq Go Ca++ from ER Ras IP3 PLCb AMP GNRPs (e.g. Sos) PIP Adenylyl cyclase (a MAPKKK) cAMP PKC Smad JNKK NIK IKK STAT JNK IkB/NFkB MAP-kinase (ERK) Caspases IkB/NFkB Cell death Elk-1 P MEKK (a MAPKKK) MAPKK (e.g.MEK) PKA TRADD FADD TRAF STAT Raf DAG Smad jun CREB JNK Gene Fos jun AP1 NFkB Gene P Elk-1 Nucleus STAT STAT Fos Gene jun AP1 Smad Smad Gene Gene Signal transduction pathways Phosphorylation is key A. Receptor tyrosine kinase (RTK) 1. ________ binds receptor 2. Receptor undergoes _______ 3. Receptor ____________ occurs 4. Receptor __________________ 5. Receptor binds _____________ 6. Adaptor protein binds ________ 7. G-protein recruits ____ 8. Raf phophorylates ____ 9. ____ phosphorylates ERK 10. ERK phosphoryates a ____________________ 11. Transcription is ____________ General pathway Fig. 6.14 B. TGF-b signalling- a simpler pathway 1. Ligand binds _______ 2. Two _______ receptors dimerize 3. _____________________ occurs 4. Receptor phosphorylates ________ 5. SMADs ___________ 6. SMADs enter _________and bind ____ 7. Transcription is _____________ Fig. 6.20 C. JAK-STAT pathway- also a simpler pathway Fig. 6.21 D. Wnt signaling If mutate B-catenin, constitutive activation of myc gene– Tumor formation Apoptosis Jacobson et al., Cell 88:347 (1997) Too much and too little Too much- ________________ disease • Alcohol-induced liver disease • Autoimmune disease • Primary biliarry cirrhosis • Wilson’s disease • Ischemia reperfusion injury • Virus hepatitis Too little- ___________ • Splenomegaly • Lymphadenopathy • Cholangiocarcinoma • Hepatocellular Carcinoma Fas-null mice Lymph nodes Spleen Apoptosis is required for normal development Elegans Mammals Fig. 6.28 Wild-type Fig. 6.27 Apaf-1 knock-out Receptor-mediated Apoptosis Cleavage of Death substrates •structural proteins (e.g. actin) •kinases (e.g. MEKK, PKC) •cell cycle proteins (pRb, PARP) •DNA repair enzymes •DNA nucleases •Anti-apoptotic proteins (Bcl-2) Caspases-3, -6 and -7 Protective Monitoring Apoptosis by ______________ Hoechst Monitoring Apoptosis by _______________ M38 Fg-14 0h 3h 7h 0h 3h 7h 5 kb 2 kb 1 kb 0.5kb Monitoring Apoptosis by _________ 1000X M38 400X Fg14 1000X Hoechst TUNEL An example of __________ signaling _________ signaling Cell 1 Delta (Ligand) Notch (receptor) Cell 2 Another example of ____________ signaling The ___________________ • The stuff between cells • Affects cell adhesion, _______________, epithelial sheet formation • Includes collagen, proteoglycans, fibronectin and laminin _______ are the _______________ for extracellular matrix molecules Integrins interact with both extracellular and intracellular scaffolds Fibronectin Integrin Actin Another form of communication_______transmission of signals through __________________ Fig. 6.38 •Does not requires a __________, only regulation of small molecules through a port •Ports are composed of _______________ Signaling pathways exhibit ____________A major challenge in biology- How to get specificity from _______________pathways Example: Two pathways direct lymphocyte development Point of _________ Fig. 6.40 LPS-mediated apoptosis: Which pathway is defective? LPB LPS FasL TNF TNFR FasR FADD Caspase 8 Sorb. CD14 RIP TRAF2 JNKK p65 p105 c-jun FADD Caspase 8 P38 MAPK NIK MEKK1, 2, 3 JNK IL1R1 TRADD P38 MAPK TPL-2 TLR-4 Calyculin A, Okadaic Acid PDTC TAK1 TRAF6 MyD88 IRAK TNF PKC EGFR IKK MEK PD098059 ERK1,2 ALLN, HMA IkB NF-kB P105 phos, degraded TGFBR SN50 Apoptosis Proteasome NF-kB-responsive genes A1, A20, ,Fas, FasL,TNF, Bcl2, TRAF1,2, c-IAP1,2 ROS
