Cell Adhesion

mchuang@ntu.edu.tw Graduate I tit t f A t G d t Institute of Anatomy and Cell Biology d C ll Bi l

1

CellCell-Cell Adhesion and Cell-Matrix Adhesion Cell-

actin filaments

adhesion belt (cadherins)

cadherin Ig CAMs integrin selectin l ti

focal contact (integrins)

integrin

Functions of Cell Adhesion

cell cycle proliferation migration

differentiation

survival

Cell Adhesion
inflammation cell shape

angiogenesis apoptosis

polarity

CELL-CELL ADHESION Cadherins E, N, P cadherins desmosomal cadherins

Ca2+- or Mg2+ -dependence

homophilic homophilic

actin filaments (via catenins) intermediate filaments (via desmoplakins, plakoglobin and other proteins) unknown unknown actin filaments

adhesion belts desmosomes

yes

Ig family members Selectins (blood cells + endothelial cells)

N-CAM, L1 P-selectin

no yes yes

homophilic or heterophilic h t hili heterophilic heterophilic

no no no

Integrins (on blood cells) LFA 1 (aLb2) LFA-1 ), Mac-1 (aMb2) CELL-MATRIX ADHESION Integrins many types

yes

heterophilic

actin filaments (via talin, vinculin, and other proteins) intermediate filaments actin filaments

focal contacts

a 6b 4 Transmembrane Proteoglycans syndecans

yes no

heterophilic heterophilic

hemidesmosomes no 4

Major families of cell-adhesion molecules

6
Annu. Rev. Pharmacol. Toxicol. 2002. 42:283323

7
Annu. Rev. Pharmacol. Toxicol. 2002. 42:283323

Significance of cytoskeletons in cell adhesion

ith t without cytoskeletal attachment
adhesion molecule Plasma membrane

No effect on cell

PULL

cytoskeleton

with cytoskeletal y attachment

Cell adhesion

PULL

Cell Cell Cell-Cell adhesion

Ig CAMs

endothelium

10

Selectin
P-selectin

Lectin domain
E-selectin se ec

EGF-like domain

L-selectin

Short consensus repeat

11

LEUKOCYTE

L-Selectin P-Selectin P Selectin E-Selectin

ENDOTHELIAL CELLS

Thrombin Histamine TNF- LPS

TNF- IL-1 IFN- LPS 12

L-Selectin

ESL 1 ESL-1

PSGL 1 PSGL-1

LEUKOCYTE

ENDOTHELIAL CELL
GlyCAM-1 CD34 MAdCAM-1 E-Selectin P-Selectin
13

INTERACTION
Selectin Protein Selectin Ligand Carbohydrate on lipids p proteins

14

Leukocyte Adhesion Deficiency II (LAD II)

Intrauterine growth retardation I t t i th t d ti Recurrent infection Mental retardation
Nat Genet. 2001. 28:69-72

Short stature Autistic features Convulsions Cerebral atrophy Microcephaly Coarse face
a 20-year-old man with LAD II

Mutation in GDP-fucose transporter GDP fucose causes no fucose at the cell surface.

15 J Clin Immunol. 2010 Mar;30(2):308-13.

Leukocyte Adhesion Deficiency III y y

16 Nature Medicine 15, 249 - 250 (2009)

Cell-ECM adhesion

17

Integrin

Cell, Vol. 110, 673687, September 20, 2002

18

Signaling transduction pathways emanating from Integrins

19
31 MAY 2002 VOL 296 p.1652-1653 SCIENCE

20
NATURE REVIEWS | MOLECULAR CELL BIOLOGY VOLUME 2 | NOVEMBER 2001 | 795

Common integrins and ECM ligands bound

21
Journal of Cell Science 115, 3729-3738 2002

Integrin binding proteins

22
Annu. Rev. Pharmacol. Toxicol. 2002. 42:283323

Integrin binding proteins

23
Annu. Rev. Pharmacol. Toxicol. 2002. 42:283323

Integrin Signaling Pathway

Integrins

24
http://stke.sciencemag.org May 31, 2002. J. Thomas Parsons

FAK
Focal Adhesion Kinase

25

26

Oncogene (2004) 23, 79287946.

Focal Adhesion Kinase (FAK)

nonreceptor t t tyrosine kinase i ki

27

NATURE REVIEWS | MOLECULAR CELL BIOLOGY VOLUME 6 | JANUARY 2005 | 59

Example of FAK function

caveolin

Focal Adhesion Kinase

P P

Shc

CrkII

Ras

C3G Rap-1

Ras
Raf

survival
B-Raf

ERK

ERK contractibility
28

Modified from Annu. Rev. Pharmacol. Toxicol. 2002. 42:283323

Multiple signaling proteins dock at Tyrosine 397 of FAK

p pY397

29
Biochimica et Biophysica Acta 1540 (2001) 1-21

30

NATURE REVIEWS | MOLECULAR CELL BIOLOGY VOLUME 6 | JANUARY 2005 | 58

4GalNAc-T3 Mock 4GalNAc T3

IB:

B
Mock 4GalNAc-T3

IB:
pY397

4GalNAc-T3

1.0 1.0 1.0

2.5 2.7 3.5

FAK 4G10 (anti-pY) PY20 (anti-pY) (anti pY)

1.0 1.0

2.5
pY576

1.7
FAK

IP: FAK (C20)

IP: FAK (C20)

D
Mock 4GalNAc-T3 pERK1/2

Mock 4GalNAc-T3 IB: pY118-paxillin

1.0

1.8
ERK1/2 -actin

1.0 1.0

1.8
pY31 paxillin pY31-paxillin

0.5
paxillin WCL

31

ILK
Integrin-Linked Kinase

32

Integrin-Linked Integrin Linked Kinase binding proteins

33
The Journal of Cell Biology, Volume 155, Number 4, November 12, 2001 505-510

ILK-PINCH-parvin (IPP) complex

34 NATURE REVIEWS | MOLECULAR CELL BIOLOGY VOLUME 7 | JANUARY 2006 | 22

Signaling through IPP complex

35 NATURE REVIEWS | MOLECULAR CELL BIOLOGY VOLUME 7 | JANUARY 2006 | 24

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

CrkII

Ras

C3G Rap-1

Ras
Raf

survival
B-Raf

ERK

ERK contractibility
38

Modified from Annu. Rev. Pharmacol. Toxicol. 2002. 42:283323

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

39

Integrin signaling to the cytoskeleton via Rho GTPases

Rho

Rac

CDC42

P cofilin
STRESS FIBERS

40
Annu. Rev. Pharmacol. Toxicol. 2002. 42:283323

Mechanism of activation of N-WASP

Active N-WASP

41
Adapted from Journal of Cell Science 114, 1801-1809, 2001

Mechanism of activation of WAVE2

42
Journal of Cell Science 114, 1801-1809, 2001

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. 42:283323

1. Activation of receptor tyrosine kinase (RTK)

Integrin aggregation and ligand binding I t i ti d li d bi di
EGFR, PDGF-R, FGFR phosphorylation

Integrin aggregation alone

PDGF-R, EGFR

Direct integrin-RTK interaction

v3 and PDGF-R, insulin receptor, VEGF-R2

Via integrin-associated cytoskeletal components

Integrin-actin-Neu RTK, integrin-FAKEGFR or PDGFR
45

Integrin regulation of growth factor receptors

46
NATURE CELL BIOLOGY VOL4 APRIL 2002 E75-76

FAK integrates growth-factor and integrin signals to promote cell migration g p g

47 Current Opinion in Genetics & Development 2004, 14:92101

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 Integrin-mediated 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 i li

50
Annu. Rev. Pharmacol. Toxicol. 2002. 42:283323