Cell Adhesion and Signaling - 國立臺灣大學homepage.ntu.edu.tw/~mchuang/Adhesion.pdf ·...
Transcript of Cell Adhesion and Signaling - 國立臺灣大學homepage.ntu.edu.tw/~mchuang/Adhesion.pdf ·...
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Transactivation
NATURE REVIEWS | CANCER VOLUME 7 | FEBRUARY 2007 | 85
Functions of Cell Adhesion
proliferation
differentiation
inflammation
angiogenesis
apoptosis
polarity
cell shape
survival
migration
cell cycle
Cell Adhesion
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CELL-CELL ADHESIONCadherins E, N, P
cadherinsCa2+- or Mg2+ -dependence
homophilic actin filaments (via catenins)
adhesion belts
desmosomalcadherins
yes homophilic intermediate filaments (via desmoplakins, plakoglobin and other proteins)
desmosomes
Ig family members N-CAM, L1 no homophilic or heterophilic
unknown no
Selectins (blood cells + endothelial cells)
P-selectin yes heterophilic unknown no
Integrins (on blood cells) LFA-1 (aLb2), Mac-1 (aMb2)
yes heterophilic actin filaments no
CELL-MATRIX ADHESIONIntegrins many types yes heterophilic actin filaments
(via talin, vinculin, and other proteins)
focal contacts
a6b4 yes heterophilic intermediate filaments
hemidesmosomes
TransmembraneProteoglycans
syndecans no heterophilic actin filaments no
Major families of cell-adhesion molecules
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Annu. Rev. Pharmacol. Toxicol. 2002. 42:283–323
Significance of cytoskeletons in cell adhesion
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No effect on cell
Cell adhesion
withoutcytoskeletalattachment
withcytoskeletalattachment
PULL
PULL
cytoskeleton
adhesion moleculePlasma membrane
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1. Tetheringand Rolling
3. Firm adhesion
4. Transmigration
Inflammatorystimulus
2. Activation
Selectins
Chemoattractants
Integrins
endothelium
Ig CAMs
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Selectin
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Short consensus repeat
EGF-like domain
Lectin domain
L-selectin
E-selectin
P-selectin
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L-Selectin
LEUKOCYTE
P-Selectin E-Selectin
ENDOTHELIAL CELLS
ThrombinHistamineTNF- αLPS
TNF- αIL-1 βIFN- γLPS
ESL-1 PSGL-1L-Selectin
LEUKOCYTE
h
ENDOTHELIAL CELL
GlyCAM-1 CD34 MAdCAM-1 E-Selectin P-Selectin
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Protein Carbohydrate
INTERACTION
Selectin Selectin Ligand
on lipids
proteins
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Summary of intracellular signaling cascades in leukocytes on L-selectin triggering
p56Lck
cell growth, survival, apoptosis
P-Ser
(J. Biol. Chem., V. 279, 34472-34480, August 13, 2004)
PKC
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Adapted from Pediatric Research 48:283-288 (2000)
Molecular Events in Transmembrane Signaling via E-selectin
E-selectin
SHP2 Shc
Grb2
Sos
Ras Raf MEK
ERK1/2
(HUVEC cell) -Tyr-PP-Tyr603-
15gene expression
(ex: c-fos)J. Biol. Chem., Vol. 276, Issue 51, 48549-48553, December 21, 2001
Regulation of transendothelial migration of colon cancer cells by E-selectin-mediated activation of p38 and ERK MAP kinases
Tremblay PL Auger FA
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, , Huot J. Oncogene. 2006 Oct 26;25(50):6563-73.
Signaling cascades initiated by ligation of either the selectins or their ligands
Calcium fluxSrc family kinasesRas activationMAP KinasesNeutral sphingomyelinase
Gene expression(ex: TNFα, IL-8, CXCR4)
Oxygen radicalgenerationCell shape changeβ2 integrin
activation
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Adapted from seminars in IMMUNOLOGY, Vol. 14, 2002: pp. 73–81
Integrin
18Cell, Vol. 110, 673–687, September 20, 2002
Signaling transduction pathways emanating from Integrins
31 MAY 2002 VOL 296 p.1652-1653 SCIENCE
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Common integrins and ECM ligands bound
Journal of Cell Science 115, 3729-3738 © 2002
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Integrin binding proteins
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Integrin binding proteins
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Integrin Signaling Pathway
Integrins
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http://stke.sciencemag.org May 31, 2002. J. Thomas Parsons
FAKFocal Adhesion Kinase
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Oncogene (2004) 23, 7928–7946.
Focal Adhesion Kinase (FAK)nonreceptor tyrosine kinase
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Modified from Annu. Rev. Pharmacol. Toxicol. 2002. 42:283–323
Example of FAK function
Focal Adhesion Kinase
ERKERK
JNK
CrkII
C3G
Rap-1
B-Raf
Raf
Shc
survival
contractibility
P P
caveolin
RasRas
Multiple signaling proteins dock at Tyrosine 397 of FAK
Biochimica et Biophysica Acta 1540 (2001) 1-21
pY397
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Scanning electron micrograph of a basal lamina in the cornea of a chick embryo
Some of the epithelial cells (E) have been removed to expose the upper surface of the matlike basal lamina (BL). A network of collagen fibrils (C) in the underlying connective tissue interacts with the lower face of the lamina. (Courtesy of Robert Trelstad.) 31
a cMock β4GalNAc-T3
Mock β4GalNAc-T3
b d
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aMock β4GalNAc-T3
0 h
32 h
Mock β4GalNAc-T302468
10 *
Mig
ratio
n ra
te (μ
m/h
)
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bMock β4GalNAc-T3
Mock β4GalNAc-T3
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BMock
IP: FAK (C20)
4G10(anti-pY)
FAK
IB:β4GalNAc-T3A
1.0 2.7
β4GalNAc-T3 IB:Mockβ4GalNAc-T3
1.0 2.5 1.0 2.5
1.0 1.7
pY397
pY576
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IP: FAK (C20)
FAK
pY118-paxillin
IB:
paxillin
pY31-paxillin
Mock β4GalNAc-T3C
1.0 1.8
1.0 0.5
PY20(anti-pY)
1.0 3.5
Dβ4GalNAc-T3Mock
1.0 1.8
pERK1/2
ERK1/2
β-actin
WCL
ILKIntegrin-Linked Kinase
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Integrin-Linked Kinase binding proteins
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The Journal of Cell Biology, Volume 155, Number 4, November 12, 2001 505-510
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ILK-PINCH-parvin (IPP) complex
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Signaling through IPP complex
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Activation of MAP kinasecascades by integrins
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Activation of MAP kinase cascades by integrins
Modified from Annu. Rev. Pharmacol. Toxicol. 2002. 42:283–323
Focal Adhesion Kinase
ERKERK
JNK
CrkII
C3G
Rap-1
B-Raf
Raf
Shc
survival
contractibility
P P
caveolin
RasRas
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Integrin regulates actin filamentsformation via Rho GTPases
(Rho, Rac, CDC42)
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Integrin signaling to the cytoskeleton via Rho GTPases
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Rho Rac CDC42
cofilinP
STRESS FIBERS
Lamellipodia
FILOPODIA
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Mechanism of activation of N-WASP
P Active N-WASP
45Adapted from Journal of Cell Science 114, 1801-1809, 2001
Mechanism of activation of WAVE2
46Journal of Cell Science 114, 1801-1809, 2001
Cooperativity between growth-factor receptors and integrins
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growth factor receptorintegrin
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2
3
integrin Receptor Tyrosine Kinase
Integrin regulates signaling in RTK/Ras/MAPK pathway
cytoplasm
nucleus
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1. Activation of receptor tyrosine kinase(RTK)
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• Integrin aggregation and ligand binding
– EGFR, PDGF-R, FGFR phosphorylation
• Integrin aggregation alone
– PDGFβ-R, EGFR
• Direct integrin-RTK interaction
– αvβ3 and PDGFβ-R, insulin receptor,
VEGF-R2
• Via integrin-associated cytoskeletal
components
– Integrin-actin-Neu RTK, integrin-FAK-
EGFR or PDGFR
Integrin regulation of growth factor receptors
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FAK integrates growth-factor and integrinsignals to promote cell migration
51Current Opinion in Genetics & Development 2004, 14:92–101
2. Coupling between upstream and downstream molecules
Between Ras-Raf
– EGFR, PDGF-R in
anchorage-dependent
cell growth
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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 cytoskeleton-
dependent (NIH 3T3 cells)
– G1 phase progression
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Examples of synergisms between integrins and RTK signaling
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