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Endocytosis in eukaryotic cell Nutrient internalization : LDLR Signal transduction Composition of the plasma membrane Cell fate determination, tissue remodeling.

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Presentation on theme: "Endocytosis in eukaryotic cell Nutrient internalization : LDLR Signal transduction Composition of the plasma membrane Cell fate determination, tissue remodeling."— Presentation transcript:

1 Endocytosis in eukaryotic cell Nutrient internalization : LDLR Signal transduction Composition of the plasma membrane Cell fate determination, tissue remodeling and motility LDLR and signaling

2 Pathways of receptor-mediated endocytosis Nat. Rev. Mole. Cell Biol. 3, 600, 2002 Rab5 Rab7 Rab11 PH6-6.5 PH AP2

3 Endocytic transport itineraries of receptor tyrosine kinases Nat. Rev. Mole. Cell Biol. 3, 600, 2002 TGF-  dissociate EGF bound Ligand free-recycle Ligand bound-recycle or to lysosome Sorting in MVBs

4 With ubiquitination—lysosome (ErbB1) Without—recycling (ErbB2) Dynamin-dependent endocytosis of RTKs

5 Shibire mutant

6 Dynamin: A Molecular Motor with Pinchase Action Shibire mutant A highly conserved tripartite GTP- binding domain is located at the N terminus PHD: pleckstrin homology domain (a membrane-binding domain) CC: coiled-coil (may act as an effector domain to activate the dynamin GTPase activity) PRD: a proline-rich domain (interact with numerous other proteins)

7 Endocytic transport itineraries of G-protein-coupled receptors Nat. Rev. Mole. Cell Biol. 3, 600, 2002  -adrenergic receptor D2 dopamine receptor: dynamin dependent and independent Different postendocytic transport

8 Desensitization and resensitization of G-protein-coupled receptors during endocytosis Nat. Rev. Mole. Cell Biol. 3, 600, 2002  -arrestin Endocytosis = Rapid resensitization

9 Termination of receptor-tyrosine-kinase signaling in multivesicular bodies Nat. Rev. Mole. Cell Biol. 3, 600, 2002 Cytoplasmic domain

10 MVBs

11 Endocytic protein complexes modified by signaling receptors Nat. Rev. Mole. Cell Biol. 3, 600, 2002 a.Clathrin b.Dynamin tyrosine phosphorylation and ubiquitylation c.Eps15 e.g. Egfr --Y phosphorylated recruits Cbl then Egfr is ubiquitylated d. Ral e Rab5 dominant negative inhibit endocytosis of Egfr and insulin receptor

12 Ubiquitination : Targeting of proteins for degradation by the proteasome

13 Nat. Rev. Mole. Cell Biol. 4, 497, 2003 The ubiquitylation pathway

14 Protein ubiquitylation Mono-ubiquitylation Multi-ubiquitylation poly-ubiquitylation Nat. Rev. Cell Biol. 2, 195, 2001

15 RTK journey to the lysosome Oncogene, 23, 2057, 2004

16 Ubiquitin and ubiquitin receptor in endosome fusion Nat. Rev. Mole. Cell Biol. 4, 497, 2003 Vps: vacuolar protein sorting Vps9=GEF Activates Vps21 to regulate Rab5 (Rabex-5) Ubiquitin interacts with Vps9 to release inhibition E3 ligase

17 Protein complexes modified by signaling receptors in endosomes Nat. Rev. Mole. Cell Biol. 3, 600, 2002 Rab 5 promote membrane fusion and endocytosis Egfr—Ras—RIN—activated Rab5 --Vps34—PI(3)P– membrane composition

18 Hypothetical model of signaling complexes in endosomes Nat. Rev. Mole. Cell Biol. 3, 600, 2002 Signaling protein found in endosomal compartment Different from plasma membrane? Small GTPases translocate to endosome with activated Egfr

19 Multiple pathways of endocytosis Cell, 115, 513, 2003

20 Endocytosis of membrane receptor UIM –ubiquitin-interacting motif Epsin Epsin15 Epsin15R PNAS, 102, 2679, 2005 Eps15 + clathrin Eps15 + ubiqutin Prolonged endosomal signaling

21 Endocytosis and cell fate determination Notch pathway Wingless pathway

22 Notch –transmembrane protein DSL family—Delta, Serrate, Lag-2 Kuzbanian—cleave Notch ECD Presenilin—cleave Notch ICD Notch signaling pathway nervous system: selection of a single neuroblast (lateral inhibition)

23 Cleavage of Notch Kuzbanian—cleave Notch ECD Presenilin—cleave Notch ICD

24 Dissociated NotchECD colocalizes with Delta in control retinas discs. shi wt redgreen red Ts—32 0 C vesicles surface vesicles Shi=dynamin Development, 127, 1373, 2000

25 The endocytosis of Notch ligands is required for notch activation Cell 124,897

26 Ligand-engaged and unliganded Notch Cell 124,897,2006

27 Creation of asymmetry in pIIa and pIIb cells 1. Notch endocytosis (Numb and  -adaptin) 2. Sanpodo (required for Notch signaling) endocytosis 3. Delta internalization to Rab11 (+) recycling endosome and recycle to plasma membrane Rab11 based mechanism is suppressed Cell 124,897,2006

28 The Endocytic Pathway as the Switch-off for Receptor Signaling Regulated Endocytic Routing Modulates Wingless Signaling in Drosophila Embryos Cell, 105, , 2001 Laurence Dubois, Magalie Lecourtois, Cyrille Alexandre, Elisabeth Hirst, and Jean-Paul Vincent

29 Intercellular signaling set up Segment boundary Developmental Biology by Scott F. Gilbert Sinauer Associates, publishers Six edition, 2000 Segments Wingless (Armadillo and engrailed) Hedgehog

30 Developmental Biology by Scott F. Gilbert Sinauer Associates, publishers Six edition, 2000 Arm/  -catenin interacts with Cadherin Colon cancer-APC Oncogenic-c-myc D-frizzled 2-receptor Dishevelled-cytosolic phosphoprotein Zw3/GSK3-Ser/Thr kinase Arm + Pan/lef1— transcription

31 A Transition in the Distribution of Wingless Red—Engrailed, Green--Wingless

32 Until early stage 10, Wingless spreads into the engrailed domain and then recedes sometime during stage 10. At stage 12, Wingless-containing vesicles are infrequently detected in engrailed-expressing cells. At this stage, rhomboid begins to be expressed at the posterior of each engrailed stripe, leading to the activation of EGFR signaling in and around its domain of expression. The zone of Rhomboid influence corresponds roughly to where denticles form at the end of embryogenesis, while Wingless signaling is associated with the absence of denticles (bald cuticle). PS, parasegment boundary; SB, segment boundary. A Transition in the Distribution of Wingless

33 An Active HRP-Wingless Fusion Protein Sp:signal peptide L: linker HRP-horseradish peroxidase Reacts with DAB— electron dense deposit 1.Unaffected by fixation 2.Stability—late endosome and lysosome E.Secreted –acts at a distance Arm-Gal4—naked D. Wg Gal4 rescues wg mutant

34 GAL4/UAS system

35 HRP-Wingless Is Preferentially Targeted to Lysosomes at the Posterior In all panels, HRP-Wingless is expressed under the control of the engrailed-gal4 driver

36 EGFR Signaling Modulates the Rate of Wingless Degradation Red-engrailed Green-Wingless enGAL4 UAS-nucLacZ; UAS-Wingless Pointed too Hg prevent of Wg spread

37 Regulated Endocytic Routing Modulates Wingless Signaling in Drosophila Embryos

38 Gene & Development, 16, 1314, 2002 Dpp forms a DV gradient in the Drosophila embryo

39 Models of morphogen gradient formation transcytosis

40 Distinct endocytic pathways regulate TGF-  receptor signaling and turnover Nat. Cell Biol.5, Smad7-smurf ubiquitylated Receptor and smad 1 /2

41 Endocytosis in tissue remodeling and cell migration

42 Endocytosis of E-cadherin regulate epithelial polarity and tissue remodeling Curr. Opin. Cell Biol. 18, , 2006 HGF activate Src phosphorylates E-cadherin E3 ligase binding ubiquitination (lysosomal degradation) Epithelial-mesenchymal transition

43 Specific cell boundaries are established : protocadherin recruits exocyst component Sec5 Curr. Opin. Cell Biol. 18, , 2006

44 Endocytosis regulates cell motility and invasiveness Cell, 124, , Rac 2.Rho at raft controlled by integrin signal 3.MT1-MMP Src phosphorylates endophilin A2, prevent endocytosis of MT1-MMP

45 Coaxing the LDL Receptor Family into the Fold Cell, Vol. 112, 289–292, February 7, 2003, Joachim Herz* and Peter Marschang* LRP6 holds the key to the entry of anthrax toxin Cell, 124, 1119, 2006 LDLR and Wnt signaling

46 LDL receptor-related protein Structural organization of LDL receptor family members Cell, 112, 289, 2003 VLDLR and ApoER2 Bind to Reelin Adaptor Dab1 recruits src and PI3 kinase to cause tau Phosphorylation Alzheimer’s disease LRP6-Wnt3 Arrow-Wg

47 Developmental Biology by Scott F. Gilbert Sinauer Associates, publishers Six edition, 2000 Arm/  -catenin interacts with Cadherin Colon cancer-APC Oncogenic-c-myc D-frizzled 2-receptor

48 Mesd: mesoderm development Wnt3 deficient mutant In ER, a molecular chaperone – Protein Folding In Mesd mutant-LRP fail to reach the cell surface –insoluble, aggregate in the ER The LDL Receptor family biosynthesis and secretion Cell, 112, 289, 2003 Coreceptor Fly: Arrow-Wg (Frizzled) Mouse: LRP6-Wnt3

49 LRP6 holds the key to the entry of Anthrax Toxin Cell, 124, , 2006 Toxin: LF-lethal factor:metalloproteinase (cleaves MAKK) EF-edema factor:adenylate cyclase PA-protective antigen (import) furin Prepore to pore (low pH) Antisense screen for LRP6 炭疽桿菌

50 Endocytosis and signaling transduction 1. When cell biology meets development: Endocytic regulation of signaling pathway Genes & Development , Signal transduction and endocytosis: close encounters of many kinds Nat. Rev. Mol. Cell Biol. 3, , Endosome dynamics during development Curr. Opin. Cell Biol. 18, , Endocytosis conducts the cell signaling orchestra Cell 124, , 2006

51 Visualization of signaling processes during endocytosis in living cells Nat. Rev. Mole. Cell Biol. 3, 600, 2002


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