Graduate Institute t of fanatomy and Cell Biology

Transcription

1 Cell Adhesion 黃敏銓 Graduate Institute t of fanatomy and Cell Biology 1

2 Cell-Cell Adhesion and Cell-Matrix Adhesion actin filaments adhesion belt (cadherins) cadherin Ig CAMs integrin selectin focal contact (integrins) integrin 2

3 Functions of Cell Adhesion cell cycle proliferation migration differentiation survival Cell Adhesion inflammation cell shape angiogenesis polarity apoptosis 3

4 CELL-CELL ADHESION Cadherins E, N, P Ca2+- or Mg2+ -dependence cadherins desmosomal cadherins homophilic actin filaments (via adhesion belts catenins) yes homophilic intermediate filaments (via desmoplakins, plakoglobin and other proteins) Ig family members N-CAM, L1 no homophilic or heterophilic hili Selectins (blood cells + endothelial cells) unknown P-selectin yes heterophilic unknown no Integrins (on blood cells) LFA-1 1(a L b 2 ), yes heterophilic actin filaments no Mac-1 (a M b 2 ) desmosomes no CELL-MATRIX ADHESION Integrins many types yes heterophilic actin filaments (via talin, vinculin, and other proteins) a 6 b 4 yes heterophilic intermediate filaments focal contacts hemidesmosomes Transmembrane syndecans no heterophilic actin filaments no Proteoglycans 4

5 Major families of cell-adhesion molecules 5

6 Annu. Rev. Pharmacol. Toxicol :

7 Annu. Rev. Pharmacol. Toxicol :

8 Significance of cytoskeletons in cell adhesion without t cytoskeletal attachment adhesion molecule Plasma membrane No effect on cell PULL cytoskeleton with cytoskeletal attachment Cell adhesion PULL 8

9 Cell-Cell adhesion 9

10 Ig CAMs endothelium 10 9

11 Selectin P-selectin Lectin domain E-selectin ec EGF-like domain L-selectin Short consensus repeat 11

12 LEUKOCYTE L-Selectin P-Selectin E-Selectin ENDOTHELIAL CELLS Thrombin Histamine TNF- LPS TNF- IL-1 IFN- LPS 12

13 L-Selectin ESL-1 PSGL-1 LEUKOCYTE h ENDOTHELIAL CELL GlyCAM-1 CD34 MAdCAM-1 E-Selectin P-Selectin 13

14 INTERACTION Selectin Selectin Ligand Protein Carbohydrate on lipids proteins 14

15 Leukocyte Adhesion Deficiency II (LAD II) Intrauterine t growth retardation ti Recurrent infection Mental retardation Short stature Autistic features Convulsions Cerebral atrophy Microcephaly Coarse face a 20-year-old man with LAD II Nat Genet :69-72 Mutation in GDP-fucose transporter causes no fucose at the cell surface. J Clin Immunol Mar;30(2):

16 Leukocyte Adhesion Deficiency III Nature Medicine 15, (2009) 16

17 Cell-ECM adhesion 17

18 Integrin Cell, Vol. 110, , September 20,

19 Signaling transduction pathways emanating from Integrins 31 MAY 2002 VOL 296 p SCIENCE 19

20 NATURE REVIEWS MOLECULAR CELL BIOLOGY VOLUME 2 NOVEMBER

21 Common integrins and ECM ligands bound 21 Journal of Cell Science 115,

22 Integrin binding proteins 22 Annu. Rev. Pharmacol. Toxicol :

23 Integrin binding proteins 23 Annu. Rev. Pharmacol. Toxicol :

24 Integrin Signaling Pathway Integrins 24 May 31, J. Thomas Parsons

25 FAK Focal Adhesion Kinase 25

26 Oncogene (2004) 23,

27 Focal Adhesion Kinase (FAK) nonreceptor tyrosine kinase NATURE REVIEWS MOLECULAR CELL BIOLOGY VOLUME 6 JANUARY

28 Example of FAK function caveolin Focal Adhesion Kinase P P Shc Ras CrkII C3G Ras survival Rap-1 B-Raf Raf ERK contractibility ERK 28 Modified from Annu. Rev. Pharmacol. Toxicol :

29 Multiple signaling proteins dock at Tyrosine 397 of FAK py Biochimica et Biophysica Acta 1540 (2001) 1-21

30 NATURE REVIEWS MOLECULAR CELL BIOLOGY VOLUME 6 JANUARY

31 A C Mock β4galnac-t IP: FAK (C20) Mock β4galnac-t3 IB: β4galnac-t3 4G10 (anti-py) PY20 (anti-py) FAK IB: B D Mock β4galnac-t IB: py397 py576 FAK IP: FAK (C20) Mock β4galnac-t3 perk1/ py118-paxillin py31-paxillin paxillin ERK1/ paxillin WCL β-actin 31

32 ILK Integrin-Linked Kinase 32

33 Integrin-Linked Kinase binding proteins The Journal of Cell Biology, Volume 155, Number 4, November 12,

34 ILK-PINCH-parvin (IPP) complex NATURE REVIEWS MOLECULAR CELL BIOLOGY VOLUME 7 JANUARY

35 Signaling through IPP complex NATURE REVIEWS MOLECULAR CELL BIOLOGY VOLUME 7 JANUARY

36 NATURE REVIEWS CANCER VOLUME 5 JANUARY

37 Activation of MAP kinase cascades by integrins 37

38 Activation of MAP kinase cascades by integrins caveolin Focal Adhesion Kinase P P Shc Ras CrkII C3G Ras survival Rap-1 B-Raf Raf ERK contractibility ERK 38 Modified from Annu. Rev. Pharmacol. Toxicol :

39 Integrin regulates actin filaments formation via Rho GTPases (Rho, Rac, CDC42) 39

40 Integrin signaling to the cytoskeleton via Rho GTPases Rho Rac CDC42 STRESS FIBERS P cofilin Annu. Rev. Pharmacol. Toxicol :

41 Mechanism of activation of N-WASP P Active N-WASP Adapted from Journal of Cell Science 114, ,

42 Mechanism of activation of WAVE2 Journal of Cell Science 114, ,

43 Cooperativity between growth-factor receptors and integrins integrin growth factor receptor 43 NATURE CELL BIOLOGY VOL 2 DECEMBER 2000 E

44 Integrin regulates signaling in RTK/Ras/MAPK pathway integrin Receptor Tyrosine Kinase 2 1 cytoplasm 3 nucleus 44 Annu. Rev. Pharmacol. Toxicol :

45 1. Activation of receptor tyrosine kinase (RTK) Integrin aggregation and ligand binding EGFR, PDGF-R, FGFR phosphorylation Integrin aggregation alone PDGF -R, EGFR Direct integrin-rtk interaction v 3 and PDGF -R, insulin receptor, VEGF-R2 Via integrin-associated cytoskeletal components Integrin-actin-Neu RTK, integrin-fak- EGFR or PDGFR 45

46 Integrin regulation of growth factor receptors NATURE CELL BIOLOGY VOL4 APRIL 2002 E

47 FAK integrates growth-factor and integrin signals to promote cell migration Current Opinion in Genetics & Development 2004, 14:

48 2. Coupling between upstream and downstream molecules Between Ras-Raf EGFR, PDGF-R in anchorage-dependent cell growth 48

49 3. Transmission of the signal from cytoplasm to nucleus J Cell Biol 2001 Apr 16;153(2): Integrin-mediated adhesion Regulates ERK Nuclear Translocation and Phosphorylation of Elk-1 Actin cytoskeletondependent (NIH 3T3 cells) G1 phase progression 49

50 Examples of synergisms between integrins and RTK signaling 50 Annu. Rev. Pharmacol. Toxicol :