3 Regulation Of Cxcr4 Signaling By Najmaldin Saki (2)

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3 Regulation Of Cxcr4 Signaling By Najmaldin Saki (2)

  1. 1. CXCR4 & SDF1 By : Najmaldin Saki 2008
  2. 4. <ul><li>chemokines </li></ul>(CXC , CC , C , CX3C) Chemokines receptors G protein-coupled receptor ( GPCR ) CXCR4 As a target in HIV Role in cancer metastasis Development Hematopoiesis Organogenesis vascularization
  3. 5. CXCR4 SDF1 CXCL12
  4. 6. <ul><li>The chemokine receptors CCR5 and CXCR4 are the primary co-receptors for HIV infection </li></ul><ul><li>NK-1R antagonists selectively inhibit HIV strains which use CCR5 as a co-receptor </li></ul><ul><li>Thus, there is a critical relationship between NK-1R and CCR5 receptors </li></ul>
  5. 7. CCR5 NK-1R Signal Transduction? Hetero- dimerization? Protein Synthesis? CXCR4 HIV Cytokines, Chemokines, CCR5, CXCR4 NK-1R Antagonists NK-1R:CCR5 Interaction in Macrophages CD4 SP
  6. 8. 1-Regulation of CXCR4 expression and function <ul><li>1.1.Transcriptional control of CXCR4 </li></ul>Basal regulation : Up regulation :NRF-1 & SP-1 Down regulation :YY1 Additional regulation Intracellular second messengers: cAMP , ca Cytokinse : IL2-IL4-IL7-IL10-IL15-TGF-1 beta-simultaneous Cd3 & CD28 Growth factors: bFGF – VEGF - EGF
  7. 9. In the other hand Inflammatory cytokinse Attenuate CXCR4 expression IL1 beta – INF gama – TNF Alpha HTLV1 Tax protein NRF1 HIV Herpes viruse 6 Target cell
  8. 10. 1.2-Regulation of CXCR4 protein expression <ul><li>Asn11 & Asn176 two potential N-linked glycosylation sites </li></ul><ul><li>Three extracellular tyrosines in CXCR4 Tyr7 & Tyr12 & Tyr21 .modification catalyzed by tyrosyl protein sulfotransferase. </li></ul><ul><li>N-linked modification , addition of a chondrotinin sulfat chain at serine 18. </li></ul>
  9. 12. 2-Regulation of CXCR4 signaling 2.1. SDF binding CCR5 CXCR4 CD26 Cathepsin G & Neutrophil elastase Protease dipeptidase SDF Neu
  10. 13. <ul><li>Upon entering the blood or lymphatic systems, if CXCR4 truly mediates metastasis,tumors would preferentially migrate and adhere to areas that highly express SDF1 </li></ul>
  11. 14. SDF CXCR4 PLC- beta PI3K Src 2.2.G-protein signaling jak STAT arrestin pERK P38 PTX Desensitization Arre 2 arre3
  12. 15. <ul><li>Regulation of signaling </li></ul><ul><li>Desensitization </li></ul><ul><li>Internalization </li></ul><ul><li>Degradation </li></ul>
  13. 16. C-tail
  14. 17. CXCR4 dysregulation in disease 1-WHIM syndrome Warts Hypogammaglobulinemia Recurent bacterial infection Myelokathexis <ul><li>Following activation,there is lack of desensitization , enhanced calcium mobilization ,and a decrease in SDF promoted internalization </li></ul>
  15. 18. 2-Cancer The expression of CXCR4 has been detected in 23 different cancers of various origins and is the most common chemokine receptor expressed on cancer cells. O2 Activation (HIF1) Hypoxia inducible factor 1 CXCR4 (VHL)von hipple lindau Breast cancer VEGF metastasis NF- k B Enhanced migration and adhision of rhabdomyosarcoma Oncoprotein PAX-FKHR Enhanced the transforming ability of breast cancer cells Oncoprotein RET/PCT
  16. 19. Involvement of CXCR4/SDF-1 system in cancer progression Pancreatic cancer Kosshiba et al., Clin. Cancer Res. 2000 Neuroblastoma Geminder et al., J. Immunol. 2001 Breast cancer Muller et al., Nature 2001 Rhabdomyosarcoma Libura et al., Blood 2002 Prostate cancer Taichman et al., Cancer Res. 2002 Colon cancer Zeelemberg et al., Cancer Res. 2003 Osteosarcoma Perissinotto et al., Clin Cancer Res. 2005 Laverdiere et al., Clin Cancer Res. 2005 N on-small cell lung cancer cells Su et al., Clin Cancer Res. 2005 E sophageal cancer Kaifi et al., J Natl Cancer Inst. 2005 Carcinomatosis of Gastric Cancer Yasumoto et al., Cancer Res. 2006 G lioma Ehtesham et al., Oncogene 2006 Melanoma Bartolome et al., Cancer Res. 2006
  17. 20. Cancer cell Y Y chemokine receptor chemokine endothelium Target tissue Non-target tissue Cancer cell Y Y endothelium different chemokine
  18. 21. The C-tail is absolutely critical for proper regulation of CXCR4
  19. 22. <ul><li>It is expected that the functional consequense of CXCR4 expression on cancer cells would be varied based on the numerous roles of the CXCR4-SDF signaling axie.for example,the combination of CXCR4 expression and interaction with stormal or nurse-like cells in chronic lymphocytic leukemia and multiple myeloma may account for resistence to spontaneous/drug induced apoptosis and cell adhesion-mediated drug resistance,essentially providing a protective niche. </li></ul>

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