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

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

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

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

4 CD43 Expression: All lymphoid cells (except erythrocytes), Epithelial tumors 45 nm CD4 123 aa serine, threonine and proline residues 60% of the molecular mass Sialic acid Galactose N-acetylgalactosamine 115 kda/135 kda Intracytoplasmic region: -no enzymatic activity - no tyrosine residues -serine and threonine residues potentially phosphorylable -Proline rich region -ERMs binding region

5 CD4 Sialyl 4 Lex L-selectin PSGL-1 E- selectin HSA SiGlec-1 CD2 2 CD83 CD33 ICAM-1 LFA-1 Transialidase T. cruzi CD43 MHC I CD8 S. gordinii Galectin-1 ACTIVATION Anti-CD43 Abs CD7 CD45 M. tuberculosis GM 1 CD3 CD4 HOMING ADHESION APOPTOSIS CD43 INFLAMMATION ANTI- ADHESION CYTOSKELETON REARRENGEMENTS PROLIFERATION

6 CD3 ζ ζ CD43 Y Y Y Y vía PLCγ vía Rho Family Y Y Y Y vía Ras vía PI3K Lck PLCγ PIP 2 IP 3 DAG PKC Ca ++ ER Calcineurin Shc Rac GTP Grb2 Vav GTP NFAT JNK NFκB p38 S h c R a s GTP G r b 2 S o s GTP R a f Jun AP-1 M e k P P E r k Fos PI3K PIP 2 PIP 3 PDK1 AKT mtor TRANSCRIPCIÓN DE GENES

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

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9 Is the order important? CD43 ERK SHP-1 adapted from Nat. Rev. Mol. Cell Biol. 2000

10 CD43 engagement prior or at the same time as the TcR results in sustained ERK phosphorylation A Time (min) IgG1/IgG2 L10 OKT3 (L10+OKT3) perk ERK perk ERK perk ERK perk ERK B Time (min) IgG1/IgG2 L10 OKT3 (L10+OKT3) pjnk JNK pjnk JNK pjnk JNK pjnk JNK C Time (min) 10 TPA perk ERK pjnk JNK L10-OKT3 perk ERK L10-OKT3 pjnk JNK OKT3-L perk ERK OKT3-L pjnk JNK

11 CD43 CD3 TCR CD3 TCR TCR CD3 CD43 PI3-K E RM Vav CD3ζ Lck Fyn SHP-1 DAG PLCγ 2 PIP 2 PKC p70s6k Ras ERK MAPKs JNK PKC IP3 Ca ++ Proliferation apoptosis

12 CD43 signals provided at the same time or prior to those of the TCR prevent the association of SHP-1 to Lck 2h

13 T cell proliferation vs anergy : the order matters? IL-2 PRODUCTION 2h 48h 7 d Proliferation IL-2

14 CD43 prior or at the same time that the TCR prevents CTLA-4 expression Proliferation Anergy -CTLA-4 -No IL-2 2h 48h CTLA-4

15 Fold change

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

17 CD3 CD43 CD3 CD43 CTLA-4 Downstream signals Zap-70 CBL CBL-b CD3ζ ERK Lck X SHP-1 T-bet Downstream signals Zap-70 CD3ζ ERK Lck SHP-1 PROLIFERATION CYTOKINES, ETC CD43+TCR CD43-TCR PROLIFERATION TCR-CD43

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

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

20 T r minos de la # de entradas bœsqueda (PubMed) CD 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

21 CD43 promotes cell transformation Colonies A and D. NIH 3T3 mock cells. B and E. NIH 3T3 CD43WT. C and F. NIH 3T3 CD43ΔIC.

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

23 CD43 enhances wound-healing

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

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