CXCR4 & SDF1By : Najmaldin Saki

2008

chemokineschemokines(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

CXCR4

SDF1CXCL12

•The chemokine receptors CCR5 and CXCR4 The chemokine receptors CCR5 and CXCR4 are the primary co-receptors for HIV infectionare the primary co-receptors for HIV infection

•NK-1R antagonists selectively inhibit HIV NK-1R antagonists selectively inhibit HIV strains which use CCR5 as a co-receptorstrains which use CCR5 as a co-receptor

•Thus, there is a critical relationship between Thus, there is a critical relationship between NK-1R and CCR5 receptorsNK-1R and CCR5 receptors

CCR5

NK-1R

Signal Transduction?

Hetero-dimerization?

Protein Synthesis?

CXCR4

HIV

Cytokines, Chemokines, CCR5, CXCR4

NK-1RAntagonists

NK-1R:CCR5 Interaction in Macrophages

CD4

SP

1-Regulation of CXCR4 expression and function1-Regulation of CXCR4 expression and function

1.1.Transcriptional control of CXCR41.1.Transcriptional control of CXCR4

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

In the other handInflammatory cytokinseAttenuate CXCR4 expression

IL1beta – INF gama – TNF Alpha

Target cell

HTLV1

Tax protein

NRF1

HIV

Herpes viruse 6

1.2-Regulation of CXCR4 protein expression

• Asn11 & Asn176 two potential N-linked glycosylation sites

• Three extracellular tyrosines in CXCR4 Tyr7 & Tyr12 & Tyr21.modification catalyzed by tyrosyl protein sulfotransferase.

•N-linked modification , addition of a chondrotinin sulfat chain at serine 18.

2-Regulation of CXCR4 signaling

2.1 .SDF binding

CCR5

CXCR4

CD26

Cathepsin G & Neutrophil elastase

Protease dipeptidase

SDF

Neu

Upon entering the blood or lymphatic systems, if CXCR4 truly mediates metastasis,tumors would preferentially migrate and adhere to areas that highly express SDF1

SDF

CXCR4

PLC-beta

PI3K

Src

2.2.G-protein signaling

jak

STAT

arrestin

pERK

P38

PTX

Desensitization

Arre 2

arre3

Regulation of signalingRegulation of signaling

•Desensitization

•Internalization

•Degradation

C-tail

CXCR4 dysregulation in diseaseCXCR4 dysregulation in disease

1-WHIM syndrome1-WHIM syndrome

Warts

Hypogammaglobulinemia

Recurent bacterial infection

Myelokathexis

Following activation,there is lack of desensitization,enhanced calcium mobilization,and a decrease in SDF promoted internalization

2-CancerThe expression of CXCR4 has been detected in 23 different cancers of various origins and is the most common chemokine receptor expressed on cancer cells.

Breast cancerBreast cancerVEGFVEGFmetastasismetastasisNF-NF-kkBB

Enhanced migration and adhision of Enhanced migration and adhision of rhabdomyosarcomarhabdomyosarcoma

Oncoprotein PAX-FKHR Oncoprotein PAX-FKHR

Enhanced the transforming ability of Enhanced the transforming ability of breast cancer cellsbreast cancer cells

Oncoprotein RET/PCTOncoprotein RET/PCT

O2

Activation (HIF1)Hypoxia inducible factor 1

CXCR4

(VHL)von hipple lindau

Pancreatic cancerPancreatic cancerKosshiba et al., Clin. Cancer Res. Kosshiba et al., Clin. Cancer Res. 20002000

NeuroblastomaNeuroblastomaGeminder et al., J. Immunol. 2001Geminder et al., J. Immunol. 2001

Breast cancer Breast cancer Muller et al., Nature 2001Muller et al., Nature 2001

RhabdomyosarcomaRhabdomyosarcomaLibura et al., Blood 2002Libura et al., Blood 2002

Prostate cancerProstate cancerTaichman et al., Cancer Res. 2002Taichman et al., Cancer Res. 2002

Colon cancerColon cancerZeelemberg et al., Cancer Res. 2003Zeelemberg et al., Cancer Res. 2003

OsteosarcomaOsteosarcomaPerissinotto et al., Clin Cancer Res. Perissinotto et al., Clin Cancer Res. 20052005

Laverdiere et al., Laverdiere et al., Clin Cancer Res. Clin Cancer Res. 20052005

NNon-small cell lung cancer cells on-small cell lung cancer cells Su et al., Clin Cancer Res. 2005Su et al., Clin Cancer Res. 2005

EEsophageal cancersophageal cancerKaifi et al., Kaifi et al., J Natl Cancer Inst. 2005 J Natl Cancer Inst. 2005

Carcinomatosis of Gastric CancerCarcinomatosis of Gastric CancerYasumoto et al., Yasumoto et al., Cancer Res. 2006 Cancer Res. 2006

GGlioma lioma Ehtesham Ehtesham et al., Oncogene 2006et al., Oncogene 2006

MelanomaMelanomaBartolome et al., Cancer Res. 2006Bartolome et al., Cancer Res. 2006

Involvement of CXCR4/SDF-1 system in cancer progression

Cancer cell

YY

chemokine receptor

chemokine

endothelium

Non-target tissue

Cancer cell

Y Yendothelium

differentchemokine

Target tissue

The C-tail is absolutely critical The C-tail is absolutely critical for proper regulation of for proper regulation of

CXCR4CXCR4

It is expected that the functional consequense It is expected that the functional consequense of CXCR4 expression on cancer cells would be of CXCR4 expression on cancer cells would be varied based on the numerous roles of the varied based on the numerous roles of the CXCR4-SDF signaling axie.for example,the CXCR4-SDF signaling axie.for example,the combination of CXCR4 expression and combination of CXCR4 expression and interaction with stormal or nurse-like cells in interaction with stormal or nurse-like cells in chronic lymphocytic leukemia and multiple chronic lymphocytic leukemia and multiple myeloma may account for resistence to myeloma may account for resistence to spontaneous/drug induced apoptosis and cell spontaneous/drug induced apoptosis and cell adhesion-mediated drug resistance,essentially adhesion-mediated drug resistance,essentially providing a protective nicheproviding a protective niche..