CAN THE CD43 MOLECULE BE CONSIDERED AS A THERAPEUTIC TAGET? Yvonne - - PowerPoint PPT Presentation

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CAN THE CD43 MOLECULE BE CONSIDERED AS A THERAPEUTIC TAGET? Yvonne Rosenstein Instituto de Biotecnologia, UNAM CD43: the molecule and its signaling capacities favors a Th1 differentiation pattern and contributes to the decision making

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CAN THE CD43 MOLECULE BE CONSIDERED AS A THERAPEUTIC TAGET? Yvonne Rosenstein Instituto de Biotecnologia, UNAM

SLIDE 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

SLIDE 3

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

SLIDE 4

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 mass Sialic acid Galactose N-acetylgalactosamine 115 kDa/135 kDa serine, threonine and proline residues Expression:

All lymphoid cells

(except erythrocytes),

Epithelial tumors

SLIDE 5

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 CD8 LF A-1 Transialidase

T. cruzi
M. tuberculosis

CD4 GM1 E- selectin CD2 2 CD33 CD83 PSGL-1 Sialyl Lex CD4 4 INFLAMMATION

S. gordinii

SLIDE 6

S h c G r b 2 S o s

R a s

GTP GTP

R a f M e k E r k

P P

Ras vía

Shc Grb2 Vav Rac

GTP GTP

vía Rho Family

Lck PLC

PIP 2 IP3 DAG PKC ER Ca

Calcineurin PI3K PIP2 PIP 3

vía PI3K vía PLCγ

JNK p38

CD3 ζ ζ

Y Y Y Y Y Y Y Y Y Y Y Y

TRANSCRIPCIÓN DE GENES PDK1 mTOR CD43

NFA T

AKT

NFκB

AP-1

Fos

Jun

SLIDE 7

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

SLIDE 8

SLIDE 9

CD43 adapted from Nat. Rev. Mol. Cell Biol. 2000

Is the order important?

ERK SHP-1

SLIDE 10

CD43 engagement prior or at the same time as the T cR results in sustained ERK phosphorylation

Time (min) 5 10 15 30 L10 OKT3 (L10+OKT3) L10-OKT3 OKT3-L10 IgG1/IgG2 pJNK 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/IgG2 pERK pERK pERK pERK pERK ERK ERK pERK 1 2 3 4 5 6 7 8 A TPA pERK ERK pJNK JNK C Time (min) 10

SLIDE 11

PI3-K E R M PKC p70S6K Lck Fyn Vav Ras MAPKs PKC PLCγ 2 IP3 Ca++ CD43 PIP2 DAG CD3 CD3 TCR TCR CD43 CD3ζ SHP-1 CD3 TCR Proliferation apoptosis ERK JNK

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CD43 signals provided at the same time or prior to those of the TCR prevent the association of SHP-1 to Lck

2h

SLIDE 13

T cell proliferation vs anergy : the order matters ?

2h 7 d Proliferation 48h

IL-2

IL-2 PRODUCTION

SLIDE 14

CD43 prior or at the same time that the TCR prevents CTLA-4 expression

2h 48h

CTLA-4

CTLA-4
No IL-2

Proliferation Anergy

SLIDE 15

Fold change

SLIDE 16

CD43 signals induce IL-12R , IFNγR and IFNγ expression

SLIDE 17

Lck CD43 CD3 Zap-70 CD3ζ SHP-1 PROLIFERA TION CYTOKINES, ETC ERK Lck CD43 CD3 Zap-70 CD3ζ SHP-1 PROLIFERA TION ERK

CD43+TCR CD43-TCR TCR-CD43

X

CTLA-4 Downstream signals Downstream signals

CBL

CBL-b

T-bet

SLIDE 18

a b a.1 a.2 a.1.2 a.1.1 b.1 b.2

SLIDE 19

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

SLIDE 20

T r minos de la bœ squeda (PubMed) # de entradas CD43 997 CD43 & tumor cells 386 CD43 & lymphomas 261 CD43 & skin 88 CD43 & lung 35 CD43 & breast 15 CD43 & colon 13 CD43 & ovary 10 CD43 & cervix 5 CD43 & thyroid 3 CD43 & metastasis 12

SLIDE 21

A and D. NIH‐3T3 mock cells. B and E. NIH‐3T3‐CD43WT. C and F. NIH‐3T3‐CD43ΔIC.

CD43 promotes cell transformation

Colonies

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Baeckstrom et al., 1995; Santamaria et al., 1996; Sikut et al., 1997; Kadaja et al., 2004; Ziprin et al., 2004

SLIDE 23

CD43 enhances wound-healing

SLIDE 24

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

SLIDE 25

Instituto de Biotecnologia Gustavo Pedraza Erika Melchy Oswaldo López Nora Fierro Amiel Olivos Monserrat Sandoval Maria Elena Bravo Nohemi Camacho Cecilia Martinez UAEM Angélica Santana Funding from:

CAN THE CD43 MOLECULE BE CONSIDERED AS A THERAPEUTIC TAGET? Yvonne Rosenstein Instituto 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:

CD43

45 nM

CD4

123 aa

60% of the molecular mass Sialic acid Galactose N-acetylgalactosamine 115 kDa/135 kDa serine, threonine and proline residues Expression:

(except erythrocytes),

NFA T

NFκB

AP-1

Fos

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 T cR results in sustained ERK phosphorylation

PI3-K E R M PKC p70S6K Lck Fyn Vav Ras MAPKs PKC PLCγ 2 IP3 Ca++ CD43 PIP2 DAG CD3 CD3 TCR TCR CD43 CD3ζ SHP-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 ?

2h 7 d Proliferation 48h

IL-2

CD43 prior or at the same time that the TCR prevents CTLA-4 expression

2h 48h

CTLA-4

Proliferation Anergy

Fold change

CD43 signals induce IL-12R , IFNγR and IFNγ expression

Lck CD43 CD3 Zap-70 CD3ζ SHP-1 PROLIFERA TION CYTOKINES, ETC ERK Lck CD43 CD3 Zap-70 CD3ζ SHP-1 PROLIFERA TION ERK

CD43+TCR CD43-TCR TCR-CD43

X

CTLA-4 Downstream signals Downstream signals

T-bet

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 la bœ squeda (PubMed) # de entradas CD43 997 CD43 & tumor cells 386 CD43 & lymphomas 261 CD43 & skin 88 CD43 & lung 35 CD43 & breast 15 CD43 & colon 13 CD43 & ovary 10 CD43 & cervix 5 CD43 & thyroid 3 CD43 & metastasis 12

CD43 promotes cell transformation

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

which a cell perceives different signals

– Cbl c pSer vs Cblc pY & SHP-1 dependent mechanism

cytokynes, cheokines and growth factors, both in normal human T cells and in non-lymphoid human tumor cells

lymphoid tumor cells

Instituto de Biotecnologia Gustavo Pedraza Erika Melchy Oswaldo López Nora Fierro Amiel Olivos Monserrat Sandoval Maria Elena Bravo Nohemi Camacho Cecilia Martinez UAEM Angélica Santana Funding from:

DGAPA/UNAM CONACYT