IL-2R & IL-15R Alice Praduroux

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1 Università degli Studi di Torino Facoltà di Biotecnologie Molecolari Anno Accademico 2006/2007 Corso di Immunologia Molecolare IL-2R & IL-15R Alice Praduroux

2 Classificazione Recettori appartenenti alla famiglia I o delle ematopoietine - motivo caratteristico WSXWS - cisteine conservate Esistono in due forme: - ancorati alla membrana - solubili

3 Struttura Eterotrimero: IL-2Rα ( CD25 o Tac ) IL-15Rα IL-2β ( p75 ) IL-15Rβ γc γc Budagian V. et al, IL-15/IL-15 receptor biology: a guided tour through an expanding universe. CGFR, 17:259, 2006

4 Affinità di legame IL-2R IL-15R -11 IL-15Rα Kd=10 M affinità elevata -9 IL-15Rβγ Kd=10 M affinità intermedia Gaffen S.L and Liu K.D, Overview of interleukin-2 function, production and clinical applications. Cytokine 28: 109, 2004 Budagian V. et al, Natural soluble interleukin-15rα is generated by cleavage that involves the tumor necrosis factor-α-converting enzyme ( TACE/ADAM17 ). J. Biol. Chem 279: 40368, 2004.

D, Overview of interleukin-2 function, production and clinical applications.

5 Ruolo delle subunità recettoriali CATENA α - legame con la citochina - incapacità di trasduzione del segnale COMPLESSO βγ - trasduzione del segnale - agisce anche in assenza della subunità α

6 IL-2Rα & IL-15Rα Budagian V. et al, IL-15/IL-15 receptor biology: a guided tour through an expanding universe. CGFR, 17:259, 2006

7 Isoforme IL-15Rα Schluns K. S. et al, The rolesof interleukin-15 receptor α: Trans-presentation, receptor component, or both? Int J Biochem Cell Biol, 37: 1567, 2005

8 Complesso βγ - Famiglia recettoriale delle ematopoietine Dominio extracellulare: - 4 cys conservate - motivo WSXWS Dominio intracitoplasmatico: - domini Box1 e Box2 - porzione variabile Gaffen S.L, Signaling domains of the interleukin 2 receptor. Cytokine, 14: 63, 2001

intracitoplasmatico: - domini Box1 e Box2 - porzione variabile

9 Espressione IL-2R & IL-15R IL-2R - linfociti T - linfociti B - cellule NK - DCs IL-15R Nel sistema immunitario: In altre cell: - linfociti T - fibroblasti - linfociti B - osteoclasti - cellule NK - cell epiteliali - neutrofili e eosinofili - cell endoteliali - DCs - cell neuronali e - mastociti e macrofagi della glia - adipociti

linfociti B - osteoclasti - cellule NK - cell epiteliali - neutrofili e eosinofili

10 Modelli di espressione del IL-15R Schluns K.S, The roles of interleukin-15 receptor α: trans-presentation, receptor component, or both? Int J Biochem Cell Biol, 37: 1567, 2005

11 Vie di trasduzione del segnale

12 1.PI3K pathway β α γ PI3K Jak 1 Jak 3 E2F AKT Bcl-2 Bad B a Bad Progressione del ciclo cellulare Bcl-2 Protezione dall apoptosi Budagian V. et al, IL-15/IL-15 receptor biology: a guided tour through an expanding universe. CGFR, 17: 259, Gaffen Sarah L. Signaling domains of the interleukin 2 receptor. Cytokine, 14: 63, 2001.

et al, IL-15/IL-15 receptor biology: a guided tour through an expanding universe.

13 2.MAPK pathway α β γ Jak 1 Jak 3 Shc Grb2 Sos GDP GTP Ras Raf MAPK Bcl-2 Bcl-xl Sopravvivenza cellulare c-fos Budagian V. et al, IL-15/IL-15 receptor biology: a guided tour through an expanding universe. CGFR, 17: 259, Gaffen Sarah L. Signaling domains of the interleukin 2 receptor. Cytokine, 14: 63, 2001.

et al, IL-15/IL-15 receptor biology: a guided tour through an expanding

14 3.STAT pathway β α γ Jak 3 Jak 1 STAT 5 STAT 5 STAT 5 STAT 5 STAT 5 STAT 5 IL-2: - IL-2Rα e IL-2 - FasL promoter geni target IL-15: - Bcl-xl - IL-4 Budagian V. et al, IL-15/IL-15 receptor biology: a guided tour through an expanding universe. CGFR, 17: 259, Gaffen Sarah L. Signaling domains of the interleukin 2 receptor. Cytokine, 14: 63, 2001.

15 Inibizione STAT pathway JAB/SOCS1/SSI-1 - scoperto come inibitore del signaling di IL-6 - azione sull IL-2 signalling: IL-2 promuove espressione di SOCS1 inibizione della fosforilazione di STAT blocco dello STAT pathway blocco trascrizione dell IL-2 FEEDBACK NEGATIVO Sporri B. et al, JAB/SOCS1/SSI-1 is an interleukin-2-induced inhibitor of IL-2 signaling. BLOOD, 97:221, 2001.

fosforilazione di STAT blocco dello STAT pathway blocco trascrizione dell IL-2 FEEDBACK

16 Recettori solubili Hanno origine a partire da 2 meccanismi principali: 1. Splicing alternativo dell mrna 2. Receptor shedding

17 IL-15Rα solubile Budagian V. et al, Natural soluble interleykin-15rα is generated by cleavage that involves the tumor necrosis factor-α-converting Enzyme ( TACE/ADAM10 ). J. Biol. Chem, 279: 40368, 2004.

18 IL-15Rα solubile Budagian V. et al, Natural soluble interleyki-15rα is generated by cleavage that involves the tumor necrosis factor-α-converting Enzyme ( TACE/ADAM10 ). J. Biol. Chem, 279: 40368, 2004.

19 IL-2Rα e cancro Uso mab daclizumab per definire il ruolo dell IL-2Rα nella tumorigenesi

20 IL-2Rα e cancro Khun D.J. And Ping Dou Q. Direct inhibition of interleukin-2 receptor α-mediated signaling pathway induces G1 arrest and apoptosis in human head-and-neck cancer cells. J. Cell. Biochem, 95: 379, 2005.

21 IL-2Rα e cancro Khun D.J. And Ping Dou Q. Direct inhibition of interleukin-2 receptor α-mediated signaling pathway induces G1 arrest and apoptosis in human head-and-neck cancer cells. J. Cell. Biochem, 95: 379, 2005.

22 IL-2Rα e cancro Overespressione IL-2Rα - Attivazione pathway per Bcl-2 - Attivazione costitutiva ciclina A Problema: resistenza ai farmaci e chemoterapici TRASFORMAZIONE NEOPLASTICA Khun D.J. And Ping Dou Q. Direct inhibition of interleukin-2 receptor α-mediated signaling pathway induces G1 arrest and apoptosis in human head-and-neck cancer cells. J. Cell. Biochem, 95: 379, 2005.

23 References Budagian V. et al, IL-15/IL-15 receptor biology: a guided tour through an expanding universe. CGFR, 17: 259, Gaffen S.L. and Liu K.D, Overview of interleukin-2 function, production and clinical application. Cytokine, 28: 109, Gaffen Sarah L, Signaling domains of the interleukin 2 receptor. Cytokine, 14: 63, Schluns K. Et al, The roles of interleukin-15 receptor α: trans-presentation, receptor component, or both? Int. J. Biochem. Cell. Biol., 37: 1567, Sporri B. et al, JAB/SOCS1/SSI-1 is an interleukin-2-induced inhibitor of IL-2 signaling. BLOOD, 97:221, Budagian V. et al, Natural soluble interleukin-15rα is generated by cleavage that involves the tumor necrosis factor-α-converting enzyme ( TACE/ADAM17). J. Biol. Chem, 279:40368, Mortier E. et al, Natural, proteolytic release of a soluble form of human IL-15 receptor α-chain that behaves as a specific, high affinity IL-15 antagonist. J. Immunol, 173: 1681, Kuhn D.J. And Ping Dou Q, Direct inhibition of interleukin-2 receptor α-mediated signaling pathway induces G1 arrest and apoptosis in human head-and-neck cancer cells. J. Cell. Biochem, 95: 379, 2005.

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