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