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CAN THE CD43 MOLECULE BE CONSIDERED AS A THERAPEUTIC TAGET?
Yvonne RosensteinInstituto de Biotecnologia, UNAM
CD43:
the molecule and its signaling capacities
favors a Th1 differentiation pattern and contributes to the decision making process of T lymphocytes
participates in non-lymphoid tumors
CD43:
the molecule and its signaling capacities
favors a Th1 differentiation pattern and contributes to the decision making process of T lymphocytes
participates in non-lymphoid tumors
Intracytoplasmic region:
-no enzymatic activity- no tyrosine residues-serine and threonine residues potentially phosphorylable-Proline rich region-ERMs binding region
CD43
45 nM CD4
123 aa
60% of the molecular massSialic acidGalactose N-acetylgalactosamine
115 kDa/135 kDa
serine,threonine andproline residues
Expression:• All lymphoid cells(except erythrocytes),• Epithelial tumors
PROLIFERATION
CD43
ADHESION
CYTOSKELETON REARRENGEMENTS
APOPTOSIS
ANTI-ADHESION
HOMING
ACTIVATION
L-selectin
CD43
ICAM-1
MHC I
SiGlec-1
Galectin-1
HSA
Anti-CD43 Abs CD7 CD45
CD3
CD8LFA-1
TransialidaseT. cruzi
M. tuberculosis CD4GM1
E-selectin
CD22
CD33
CD83PSGL-1
Sialyl LexCD44
INFLAMMATION
S. gordinii
S h cG r b 2
S o s
R a s
GTP
GTP
R a f
M e k
E r k
P
P
Rasvía
ShcGrb2
Vav
Rac
GTP
GTP
vía Rho Family
Lck PLCγ PIP2
IP3 DAG
PKC
ERCa++
Calcineurin
PI3K PIP2 PIP3
vía PI3Kvía PLCγ
JNK p38
CD3ζ ζ
YY
YY
YY
YY
YY
YY
TRANSCRIPCIÓN DE GENES
PDK1
mTOR
CD43
NFAT
AKT
NFκBAP-1
FosJun
CD43:
the molecule and its signaling capacities
favors a Th1 differentiation pattern and contributes to the decision making process of T lymphocytes
participates in non-lymphoid tumors
CD43
adapted from Nat. Rev. Mol. Cell Biol. 2000
Is the order important?
ERK SHP-1
CD43 engagement prior or at the same time as the TcR results in sustained ERK phosphorylation
Time (min) 5 10 15 30
L10
OKT3
(L10+OKT3)
L10-OKT3
OKT3-L10
IgG1/IgG2pJNK
JNK
pJNK
JNK
pJNK
JNK
pJNK
JNK
pJNK
JNK
pJNK
JNK
B
1 2 3 4
ERK
ERK
ERK
ERK
Time (min) 0 2 5 10 15 30 60 120
L10
OKT3
(L10+OKT3)
L10-OKT3
OKT3-L10
IgG1/IgG2pERK
pERK
pERK
pERK
pERK
ERK
ERK
pERK
1 2 3 4 5 6 7 8
A
TPA
pERKERK
pJNKJNK
C
Time (min) 10
PI3-KERM
PKC
p70S6K
Lck Fyn
Vav
Ras MAPKs PKC
PLCγ 2
IP3
Ca++
CD43
PIP2DAG
CD3CD3
TCR TCRCD43
CD3ζSHP-1
CD3
TCR
Proliferation apoptosis
ERK JNK
CD43 signals provided at the same time or prior to those of the TCR prevent the association of
SHP-1 to Lck
2h
T cell proliferation vs anergy : the order matters ?
2h7 d Proliferation
48h IL-2
IL-2 PRODUCTION
CD43 prior or at the same time that the TCR prevents CTLA-4 expression
2h48h CTLA-4
-CTLA-4
-No IL-2
Proliferation Anergy
Fold change
CD43 signals induce IL-12R , IFNγR and IFNγ expression
Lck
CD43CD3
Zap-70
CD3ζ
SHP-1
PROLIFERATIONCYTOKINES, ETC
ERK
Lck
CD43CD3
Zap-70
CD3ζ SHP-1
PROLIFERATION
ERK
CD43+TCRCD43-TCR
TCR-CD43
X
CTLA-4
Downstream signals
Downstream signals
CBL
CBL-b
T-bet
a b
a.1 a.2
a.1.2a.1.1
b.1
b.2
CD43:
the molecule and its signaling capacities
favors a Th1 differentiation pattern and contributes to the decision making process of T lymphocytes
participates in non-lymphoid tumors
T r minos de labœsqueda (PubMed)
# de entradas
CD43 997CD43 & tumor cells 386CD43 & lymphomas 261CD43 & skin 88CD43 & lung 35CD43 & breast 15CD43 & colon 13CD43 & ovary 10CD43 & cervix 5CD43 & thyroid 3CD43 & metastasis 12
A and D. NIH‐3T3 mock cel ls.
B and E. NIH‐3T3‐CD43WT.
C and F. NIH‐3T3‐CD43ΔIC.
CD43 promotes cell transformation
Col
onie
s
Baeckstrom et al., 1995; Santamaria et al., 1996; Sikut et al., 1997; Kadaja et al., 2004; Ziprin et al., 2004
CD43 enhances wound-healing
Conclusions
• CD43 senses the cell’s environment• The quality of the cell’s response can reflect the order with
which a cell perceives different signals– Cbl c pSer vs Cblc pY & SHP-1 dependent mechanism
• CD43 promotes a Th1 response• CD43-mediated signals lead to the synthesis of numerous
cytokynes, cheokines and growth factors, both in normal human T cells and in non-lymphoid human tumor cells
• CD43 favors transformation/proliferation/locomotion of non lymphoid tumor cells
Instituto de Biotecnologia
Gustavo Pedraza
Erika MelchyOswaldo López
Nora FierroAmiel OlivosMonserrat SandovalMaria Elena BravoNohemi CamachoCecilia Martinez
UAEM
Angélica Santana
Funding from:
DGAPA/UNAMCONACYT