Cell Adhesion 黃敏銓 mchuang@ntu.edu.tw Graduate Institute t of fanatomy and Cell Biology 1
Cell-Cell Adhesion and Cell-Matrix Adhesion actin filaments adhesion belt (cadherins) cadherin Ig CAMs integrin selectin focal contact (integrins) integrin 2
Functions of Cell Adhesion cell cycle proliferation migration differentiation survival Cell Adhesion inflammation cell shape angiogenesis polarity apoptosis 3
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
Major families of cell-adhesion molecules 5
Annu. Rev. Pharmacol. Toxicol. 2002. 42:283 323 6
Annu. Rev. Pharmacol. Toxicol. 2002. 42:283 323 7
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
Cell-Cell adhesion 9
Ig CAMs endothelium 10 9
Selectin P-selectin Lectin domain E-selectin ec EGF-like domain L-selectin Short consensus repeat 11
LEUKOCYTE L-Selectin P-Selectin E-Selectin ENDOTHELIAL CELLS Thrombin Histamine TNF- LPS TNF- IL-1 IFN- LPS 12
L-Selectin ESL-1 PSGL-1 LEUKOCYTE h ENDOTHELIAL CELL GlyCAM-1 CD34 MAdCAM-1 E-Selectin P-Selectin 13
INTERACTION Selectin Selectin Ligand Protein Carbohydrate on lipids proteins 14
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. 2001. 28:69-72 Mutation in GDP-fucose transporter causes no fucose at the cell surface. J Clin Immunol. 2010 Mar;30(2):308-13. 15
Leukocyte Adhesion Deficiency III Nature Medicine 15, 249-250 (2009) 16
Cell-ECM adhesion 17
Integrin Cell, Vol. 110, 673 687, September 20, 2002 18
Signaling transduction pathways emanating from Integrins 31 MAY 2002 VOL 296 p.1652-1653 SCIENCE 19
NATURE REVIEWS MOLECULAR CELL BIOLOGY VOLUME 2 NOVEMBER 2001 795 20
Common integrins and ECM ligands bound 21 Journal of Cell Science 115, 3729-3738 2002
Integrin binding proteins 22 Annu. Rev. Pharmacol. Toxicol. 2002. 42:283 323
Integrin binding proteins 23 Annu. Rev. Pharmacol. Toxicol. 2002. 42:283 323
Integrin Signaling Pathway Integrins 24 http://stke.sciencemag.org May 31, 2002. J. Thomas Parsons
FAK Focal Adhesion Kinase 25
Oncogene (2004) 23, 7928 7946. 26
Focal Adhesion Kinase (FAK) nonreceptor tyrosine kinase NATURE REVIEWS MOLECULAR CELL BIOLOGY VOLUME 6 JANUARY 2005 59 27
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. 2002. 42:283 323
Multiple signaling proteins dock at Tyrosine 397 of FAK py397 29 Biochimica et Biophysica Acta 1540 (2001) 1-21
NATURE REVIEWS MOLECULAR CELL BIOLOGY VOLUME 6 JANUARY 2005 58 30
A C Mock β4galnac-t3 1.0 2.5 1.0 2.7 1.0 3.5 IP: FAK (C20) Mock β4galnac-t3 IB: β4galnac-t3 4G10 (anti-py) PY20 (anti-py) FAK IB: B D Mock β4galnac-t3 1.0 2.5 1.0 1.7 IB: py397 py576 FAK IP: FAK (C20) Mock β4galnac-t3 perk1/2 1.0 1.8 py118-paxillin py31-paxillin paxillin 1.0 1.8 ERK1/2 1.0 0.5 paxillin WCL β-actin 31
ILK Integrin-Linked Kinase 32
Integrin-Linked Kinase binding proteins The Journal of Cell Biology, Volume 155, Number 4, November 12, 2001 505-510 33
ILK-PINCH-parvin (IPP) complex NATURE REVIEWS MOLECULAR CELL BIOLOGY VOLUME 7 JANUARY 2006 22 34
Signaling through IPP complex NATURE REVIEWS MOLECULAR CELL BIOLOGY VOLUME 7 JANUARY 2006 24 35
NATURE REVIEWS CANCER VOLUME 5 JANUARY 2005 60 36
Activation of MAP kinase cascades by integrins 37
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. 2002. 42:283 323
Integrin regulates actin filaments formation via Rho GTPases (Rho, Rac, CDC42) 39
Integrin signaling to the cytoskeleton via Rho GTPases Rho Rac CDC42 STRESS FIBERS P cofilin Annu. Rev. Pharmacol. Toxicol. 2002. 42:283 323 40
Mechanism of activation of N-WASP P Active N-WASP Adapted from Journal of Cell Science 114, 1801-1809, 2001 41
Mechanism of activation of WAVE2 Journal of Cell Science 114, 1801-1809, 2001 42
Cooperativity between growth-factor receptors and integrins integrin growth factor receptor 43 NATURE CELL BIOLOGY VOL 2 DECEMBER 2000 E225-229
Integrin regulates signaling in RTK/Ras/MAPK pathway integrin Receptor Tyrosine Kinase 2 1 cytoplasm 3 nucleus 44 Annu. Rev. Pharmacol. Toxicol. 2002. 42:283 323
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
Integrin regulation of growth factor receptors NATURE CELL BIOLOGY VOL4 APRIL 2002 E75-76 46
FAK integrates growth-factor and integrin signals to promote cell migration Current Opinion in Genetics & Development 2004, 14:92 101 47
2. Coupling between upstream and downstream molecules Between Ras-Raf EGFR, PDGF-R in anchorage-dependent cell growth 48
3. Transmission of the signal from cytoplasm to nucleus J Cell Biol 2001 Apr 16;153(2):273-82 Integrin-mediated adhesion Regulates ERK Nuclear Translocation and Phosphorylation of Elk-1 Actin cytoskeletondependent (NIH 3T3 cells) G1 phase progression 49
Examples of synergisms between integrins and RTK signaling 50 Annu. Rev. Pharmacol. Toxicol. 2002. 42:283 323