TABLE 1

Summary of CXCR4 signaling

Primary	Secondary	Function	Studied System	Reference
G protein–dependent signaling
Gα_i1, Gα_i2, Gα_i3	PI3K/Akt, inhibition of cAMP production	Cell survival and migration	HEK293 cells	Quoyer et al., 2013
			Metastatic basal-like breast cancer cells	Yagi et al., 2011
			T and B cells	Shi et al., 2007
Gα_i1, Gα_i2, Gα_i3, Gα_o	CXCR4 couples more effectively to Gα_i1 and Gα_i2 than to Gα_i3 and Gα_o		SF9 cells	Kleemann et al., 2008
Gα₁₃	Activation of Rho	Migration	Jurkat T cells	Tan et al., 2006
			Metastatic basal-like breast cancer cells	Yagi et al., 2011
		Trafficking of CXCR4 into endosomes	Human PBMC T cells	Kumar et al., 2011
Gα_q	Activation of PLC-β subfamily		Activation in dendritic cells and granulocytes	Soede et al., 2001
			No activation in T and B cells	Shi et al., 2007
G protein–independent signaling
β-arrestin-1	Attenuation of G protein signaling	Reduced inhibition of cAMP production	HEK293 cells	Cheng et al., 2000
	Increased internalization of CXCR4 (only with GRK2)		HEK293 cells	Cheng et al., 2000
β-arrestin-2	Attenuation of G protein signaling	Reduced inhibition of cAMP production	HEK293 cells	Cheng et al., 2000
	Increased internalization of CXCR4		HEK293 cells	Cheng et al., 2000
	Desensitization	Decreased G protein signaling	Lymphocytes	Fong et al., 2002
	p38-MAPK	Chemotaxis	HeLa cells	Sun et al., 2002
Influence on signaling due to coexpression/oligomerization
Influence on/oligomer with…	Effect	Secondary effect
CXCR4 (homomer)	Involved in CXCL12-mediated migration	HEK293 cells, HeLa cells, human nonsmall lung carcinoma cell line (NCI-H2126)		Wang et al., 2006
	CXCL12-mediated G protein signaling		T-Rex 293 cells	Ge et al., 2017
	Dimers internalize more than monomers		T-Rex 293 cells	Ge et al., 2017
	Nanoclusters implicated in signaling		Human T-cells	Martínez-Muñoz et al., 2018
CCR2	Gα_z activation → Ca²⁺ mobilization		HEK293 cells	Armando et al., 2014
	Negative binding cooperativity between CXCR4 and CCR2		CHO-K1 cells, primary leukocytes	Sohy et al., 2007
CCR7	Facilitates HIV infection		CD4 T-cells	Hayasaka et al., 2015
CCR5	Heteromer loses interaction with NHERF1		HEK293 cells	Hammad et al., 2010
CXCR3	Heteromer recruits β-arrestin-2		HEK293 cells	Watts et al., 2013
	Negative binding cooperativity of CXCR3 onto CXCR4		HEK293 cells	Watts et al., 2013
α₁-AR	β-arrestin-2 recruitment to CXCR4		HEK293 cells	Gao et al., 2018
	Internalization of CXCR4		Human vascular smooth muscle cells	Gao et al., 2018
	Reduced migration of CXCR4 toward CXCL12		Human vascular smooth muscle cells	Gao et al., 2018
	Activating CXCR4 potentiates effect of α₁-AR agonists		Rat and human vascular smooth muscle cells	Tripathi et al., 2015
μ-OR	CXCL12 decreases effect of antinociceptive drugs		In vivo (mice)	Chen et al., 2007
δ-OR	CXCL12 decreases effect of antinociceptive drugs		In vivo (mice)	Chen et al., 2007
			MM-1, IM-9, HEK293, Jurkat, T-cell leukemia cell lines,	Pello et al., 2008
			Human primary monocytes
κ-OR	Cross-desensitization between CXCR4 and κ-OR		Jurkat T cells, primary human neutrophils, murine B cells, mice	Finley et al., 2008
BILF1 (viral)	Impairs G protein signaling by CXCR4		HEK293 cells	Nijmeijer et al., 2010
ACKR3	ACKR3 scavenges CXCL12 from CXCR4	Fine tuning of primordial germ cell migration	Zebrafish	Boldajipour et al., 2008
			Daudi cells, MDCK, HeLa cells, Raji B cells, HUVECs, zebrafish, mouse hearts, human umbilical cords	Naumann et al., 2010
		Creating chemokine gradient for migration		Donà et al., 2013
	ACKR3 defines directionality of migration		Zebrafish lateral line primordium	Dambly-Chaudière et al., 2011
	ACKR3 negatively modulates CXCR4-mediated lymphocyte integrin adhesiveness		T lymphocytes, CD34+ cells	Hartmann et al., 2008
	Potentiation of Ca²⁺ flux^a		HEK293 cells	Sierro et al., 2007
	Negative modulation of Ca²⁺ flux^a		HEK293 cells	Levoye et al., 2009
	Delay of ERK phosphorylation		HEK293 cells	Sierro et al., 2007
	Enhancement of p38 MAPK and SAPK pathways		HEK293 cells	Decaillot et al., 2011
	Heteromer constitutively recruits β-arrestin-2^a	Enhanced cell migration^a	HEK293 cells, MDA-MB-231, U87 cells	Decaillot et al., 2011
	Reduced inhibition of cAMP production		HEK293 cells	Decaillot et al., 2011
	Decreased potency for ³⁵GTPγS binding after CXCR4 activation		HEK293 cells	Levoye et al., 2009
	ACKR3 inhibits migration by CXCR4 for low CXCL12 dose^a		T lymphocytes	Levoye et al., 2009

↵^a Controversies between studies.
³⁵GTPγS, guanosine 5′-O-(3-[³⁵S]thio)triphosphate; MAPK, mitogen-activated protein kinase; OR, opioid receptor; PBMC, peripheral blood mononuclear cell; PI3K, phosphoinositide 3-kinase; PLC-β, phospholipase C-β; SAPK, stress-activated protein kinase.