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Last Class: Cytoskeleton

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Presentation on theme: "Last Class: Cytoskeleton"— Presentation transcript:

1 Last Class: Cytoskeleton
1. Cytoskeleton components: Microtubules Actin Filaments Intermediate Filaments 2. The regulation of microtubules and Actin filaments 3. Molecular Motors 4. Cell behaviors related to cytoskeleton

2 Cell Adhesion on Extracellular Matrix (ECM)

3 Cells surrounded by ECM
(macromolecules consisting of proteins and polysacchrides) Embryonic chick limb bud

4 Connective Tissue underlying an epithelium
Fibroblast, primary cell secreting ECM

5 Fibroblasts in Connective Tissue
With Collagen fibers (SEM image of rat cornea, no elastic fiber existing, hyaluronan, proteoglycans and glycoproteins have been removed by enzymes and acids)

6 ECM Glycosaminoglycans (GAGs) covalently linked to protein, proteoglycans forming gels Fibrous proteins: collagen, elastin, fibronectin, Laminin.

7 The repeating disaccharide sequence of a GAG
Sulfate, carboxyl groups, negative charges

8 GAGs Hyaluronan Chondroitin sulfate and dermatan sulfate
Heparan sulfate Keratan sulfate

9 The relative dimensions and volumes of different molecules
Very stiff and hydrophilic, can’t be packed Negative charge->cation, Na+ ->water molecules->swelling pressure->compression resistent

10 The repeating sequence of hyoluronan
Single chain of 25,000 sugars; No sulfate

11 The linkage of GAG to protein, the assembly of proteoglycan
Start from a serine, 4 saccharide and GAG Except hyalurona

12 Diversity of Proteoglycans
Membrane-bound ribosome-> endoplasmic reticulum ->golgi apparatus

13 Non-covalently bound to hyaluronan chains
Aggrecan aggregates Non-covalently bound to hyaluronan chains Just like decorin decorates collagen fibrils

14 Proteoglycan functions
Constrain the range of embedded protein actions Affect embedded protein activities Control embedded protein release rate Prevent embedded protein degradation Control the local concentration of embedded proteins Function as co-receptors


16 Collagen, elastin, fibronectin, laminin
Fibrous Proteins: Collagen, elastin, fibronectin, laminin

17 Glycine, proline, hydroxyproline
Collagen Molecules Glycine, proline, hydroxyproline Triple helix (three fibers interwined together)

18 Fibroblasts surrounded by collagen fibrils (high order polymers)
Embryonic chick skin Fibroblasts surrounded by collagen fibrils (high order polymers)

19 Degraded fragment of XVII, endostatin, inhibits angiogenesis and hence tumor growth

20 Crosslinking of collagen fibrils
Deaminated by lysyl oxidase to yield aldehyde groups, spontaneous covelent bond between aldehyde groups (about every 67 nm) If crosslink is broken, collagen is easy to tear

21 The Life of Collagen fibril


23 Collagen fibrils form collagen fibers

24 Collagen fibrils in the tadpole skin. Tendon and bone are different
Fibril-associated collagen helps the organization of fibrils to resist tensile force. Collagen fibrils in the tadpole skin. Tendon and bone are different

25 Cells help the organization of collagen fibrils
Two embryonic chick hearts at the ends and collagen gel in the center Hearts full of fibroblasts and heart muscle cells

26 Elastic Fibers consisting of Elastin (for tissue elasticity)
Vessel Walls: EM image of dog aorta

27 Stretching of a network of elastin molecules
Elastin is highly hydrophobic Mainly two features: hydrophobic and cross-linked segments Hydrophobic segments provide elasticity Cross-linking provides stability

28 Fibronectin (crucial for angiogenesis)
A glycoprotein dimer connected by disulfite bonds at one end Can exist in soluble or fibrillar forms

29 Red: fibronectin fibrils Green: actin filament bundles
Co-alignment of extracellular fibronectin fibrils and intracellular actin filament bundles Red: fibronectin fibrils Green: actin filament bundles Not only important for adhesion, but also for migration

30 Laminin (consisting of three polypeptides a, b, g)

31 A thin, flexible mats underlying all epithelial cells and tubes
3 kinds of Basal Laminae A thin, flexible mats underlying all epithelial cells and tubes Not only for structural support and filtering, but also determine cellular functions

32 Basal Laminae in the cornea of a chick embryo
Usually synthesized by the cells seeded on it Most laminar consists of type IV collagen, laminin and nidogen (enactin)

33 A molecular structure Model of basal Laminae

34 Function of Basal Laminae in neuromuscular junctions (besides the supporting or filtering functions)
Muscle cells: laminin; neuronal cells: agrin (heparan sulfate proteoglycan)

35 Cells communicate through ECM to affect Cell shape

36 ECM affects Cell survival and proliferation

37 Cancer Cells and ECM Degradation
Matrix metalloproteinase, serine protease Proteases bound on cell surface receptor Controlling of protease activity: 1. local activation; 2. surface receptor binding; 3. inhibitor secretion tPA: tissue-type plasminogen activator; uPA: urokinase-type plasminogen activator

38 Transmembrane heterodimers
ECM Receptors Integrins Transmembrane heterodimers 20 nm above cell surface, dependent on Ca2+ and Mg2+ Integrins couple ECM to cytoskeleton through cytosolic proteins, talin, a-atinin, paxillin, filamin, vinculin


40 Inside-out Signaling for Integrins

41 Outside-in Signaling of integrins
FAK, a key molecule for integrin functions FAK can bind to Talin which associates with integrin b subunit, to paxillin which associates with integrin a subunit

42 Matrix-dependent cell survival in the formation of proamniotic cavity
During embryonic development


44 Summary 1. ECM components: glycosaminoglycans (GAGs) and fibrous proteins GAGs: Hyaluronan; Chondroitin sulfate and dermatan sulfate; Heparan sulfate; Keratan sulfate Fibrous proteins: collagen, elastin, fibronectin, laminin 2. basal laminae 3. Cell-ECM interaction, ECM degration 4. ECM receptor, integrins

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