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Endocytosis in eukaryotic cell

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Presentation on theme: "Endocytosis in eukaryotic cell"— 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
AP2 Rab5 PH6-6.5 Rab11 Rab7 PH Nat. Rev. Mole. Cell Biol. 3, 600, 2002

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

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

5 Dynamin-dependent endocytosis of RTKs
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
b-adrenergic receptor D2 dopamine receptor: dynamin dependent and independent Different postendocytic transport Nat. Rev. Mole. Cell Biol. 3, 600, 2002

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

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

10 MVBs

11 Endocytic protein complexes modified by signaling receptors
Clathrin Dynamin tyrosine phosphorylation and ubiquitylation 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 Nat. Rev. Mole. Cell Biol. 3, 600, 2002

12 Ubiquitination : Targeting of proteins for degradation by the proteasome

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

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

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

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

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

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

21 Endocytosis and cell fate determination
Notch pathway Wingless pathway

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

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

24 Dissociated NotchECD colocalizes with Delta in control retinas discs.
wt shi Ts—320C red green green red Shi=dynamin surface vesicles vesicles 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 a-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
Segments Wingless (Armadillo and engrailed) Hedgehog Developmental Biology by Scott F. Gilbert Sinauer Associates, publishers Six edition, 2000

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

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

32 A Transition in the Distribution of Wingless
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.

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

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 Hg prevent of Wg spread enGAL4 UAS-nucLacZ; UAS-Wingless Pointed too

37 Regulated Endocytic Routing Modulates Wingless Signaling in Drosophila Embryos

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

39 Models of morphogen gradient formation
transcytosis

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

41 Endocytosis in tissue remodeling
and cell migration

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

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

44 Endocytosis regulates cell motility and invasiveness
Rac Rho at raft controlled by integrin signal MT1-MMP Src phosphorylates endophilin A2, prevent endocytosis of MT1-MMP Cell, 124, , 2006

45 LDLR and Wnt signaling 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

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

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

48 The LDL Receptor family biosynthesis and secretion
Coreceptor Fly: Arrow-Wg (Frizzled) Mouse: LRP6-Wnt3 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 Cell, 112, 289, 2003

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

50 Endocytosis and signaling transduction
1. When cell biology meets development: Endocytic regulation of signaling pathway Genes & Development , 2002 2. Signal transduction and endocytosis: close encounters of many kinds Nat. Rev. Mol. Cell Biol. 3, , 2002 3. Endosome dynamics during development Curr. Opin. Cell Biol. 18, , 2006 4. 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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