Modulation of CXCR4-Mediated Gi1 Activation by EGF Receptor and GRK2

Neves, Maria G. P. M. S.; Perpiñá-Viciano, Cristina; Penela, Petronila; Hoffmann, Carsten; Mayor, Federico

doi:10.1021/acsptsci.0c00021

Cited by 4 publications

(7 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Using a library of phosphomimicking mutants in a series of assays to interrogate some of the most upstream (receptor recruitment and trimer dissociation) as well as downstream (cAMP inhibition and chemotaxis) events in canonical Gi/GPCR signaling, we show that the phosphomodifications predominantly inhibit ligand-induced signaling with some of them also promoting constitutive Gβγ signaling. These findings illuminate the basis for some poorlyunderstood observations by others that growth factors (EGF and IGF1) inhibit Gi coupling to and activation by GPCRs (CXCR4) (30,51). We also show that the mechanism(s) for signal inhibition differs based on the location of the phosphosites within the G protein (see Figure 7c; Table 3-columns #9-10).…”

Section: Discussionsupporting

confidence: 79%

See 1 more Smart Citation

Phosphorylation of Gαi shapes canonical Gα(i)βγ/GPCR signaling

Roy

Silas

Ghassemian³

et al. 2022

Preprint

View full text Add to dashboard Cite

A long-standing question in the field of signal transduction is to understand the interplay between distinct signaling pathways that control cell behavior. For growth factors and heterotrimeric G proteins, the two major signaling hubs in eukaryotes, the mechanisms of independent signal transduction have been extensively characterized; however, if/how they may cross talk remains obscure. Here we use linear-ion-trap mass spectrometry in combination with cell-based biophysical, biochemical, and phenotypic assays to chart at least three distinct ways in which growth factors may impact canonical Gα(i)βγ signaling downstream of a GPCR (CXCR4) via phosphorylation of Gαi. Phosphomimicking mutations in a cluster of residues in the αE helix (Y154/155) result in the suppression of agonist-induced Gα(i) activation while promoting constitutive Gβγ signaling; others in the P-loop (S44, S47, T48) suppress Gi activation entirely thus completely segregating the growth factor and GPCR pathways. While most phosphoevents appear to impact, as expected, the core properties of Gα(i) (conformational stability, nucleotide binding, Gβγ association and release, etc.), one phosphomimicking mutation promoted mislocalization of Gαi from the plasma membrane: a novel and unexpected mechanism of GPCR signal suppression. A phosphomutation of C-terminal Y320 was sufficient to orchestrate such suppression by protein compartmentalization. Findings not only elucidate how growth factor and chemokine signals crosstalk through phosphomodulation of Gαi, but also how such crosstalk may generate signal diversity.

show abstract

Section: Discussionsupporting

confidence: 79%

“…; and (ii) How might these phosphoevents impact the ability of canonical GPCRs to transduce signals via Gi? Furthermore, although growth factors (EGF and IGF1) were found to inhibit Gi coupling to and activation by GPCRs (CXCR4)(26, 30), mechanisms for such uncoupling/deactivation remain elusive.…”

Section: Introductionmentioning

confidence: 99%

Phosphorylation of Gαi shapes canonical Gα(i)βγ/GPCR signaling

Roy

Silas

Ghassemian³

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Since GRK2 is a positive modulator of GF-RTK signaling [ 26 ] in addition to its role in GPCR regulation [ 16 , 21 , 43 ], we assessed its role in CXCR4/ACKR3 and EGFR family signaling and crosstalk in MDA-MB-361 cells by using different approaches involving pharmacological treatments with CMPD101, an inhibitor of GRK2/3 kinase activity, and heterologous expression of extra levels of wild-type GRK2. The low CXCL12-induced ERK1/2 activation was not significantly altered in the presence of CMPD101 ( Figure 5 B).…”

Section: Resultsmentioning

confidence: 99%

“…Since we find that GRK2 plays a relevant role in ErbB-CXCR4/ACKR3 crosstalk mechanism along with c-Src, it is tempting to suggest that these proteins are functionally related in this process. In support of this notion, both EGFR or GPCR/β-arrestin/Src cascades are known to converge in phosphorylating GRK2 on tyrosine residues [ 23 , 64 ], and GRK2 and EGFR can modulate CXCR4-mediated Gi activation in HEK-293 cells by mechanisms involving tyrosine phosphorylation [ 43 ].…”

Section: Discussionmentioning

confidence: 99%

Crosstalk between CXCR4/ACKR3 and EGFR Signaling in Breast Cancer Cells

Neves

Marolda

Mayor

et al. 2022

IJMS

Self Cite

View full text Add to dashboard Cite

A better understanding of the complex crosstalk among key receptors and signaling pathways involved in cancer progression is needed to improve current therapies. We have investigated in cell models representative of the major subtypes of breast cancer (BC) the interplay between the chemokine CXCL12/CXCR4/ACKR3 and EGF receptor (EGFR) family signaling cascades. These cell lines display a high heterogeneity in expression profiles of CXCR4/ACKR3 chemokine receptors, with a predominant intracellular localization and different proportions of cell surface CXCR4+, ACKR3+ or double-positive cell subpopulations, and display an overall modest activation of oncogenic pathways in response to exogenous CXCL12 alone. Interestingly, we find that in MDA-MB-361 (luminal B subtype, Her2-overexpressing), but not in MCF7 (luminal A) or MDA-MB-231 (triple negative) cells, CXCR4/ACKR3 and EGFR receptor families share signaling components and crosstalk mechanisms to concurrently promote ERK1/2 activation, with a key involvement of the G protein-coupled receptor kinase 2 (GRK2) signaling hub and the cytosolic tyrosine kinase Src. Our findings suggest that in certain BC subtypes, a relevant cooperation between CXCR4/ACKR3 and growth factor receptors takes place to integrate concurrent signals emanating from the tumor microenvironment and foster cancer progression.

show abstract

“…New ways of activating and transmitting the intracellular signal involved in cancer are constantly being discovered. Data indicates that one route of RTKs activation may be through agonists of G protein–coupled receptors (GPCRs) [ 8 , 9 , 10 ]. This phenomenon is called transactivation, and is considered to be an important pathway, involved in growth–promoting activity of GPCR ligands [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

ELTD1—An Emerging Silent Actor in Cancer Drama Play

Sevastre

Buzatu

Baloi

et al. 2021

IJMS

View full text Add to dashboard Cite

The epidermal growth factor, latrophilin, and seven transmembrane domain–containing protein 1 (ELTD1), is a member of the G–protein coupled receptors (GPCRs) superfamily. Although discovered in 2001, ELTD1 has been investigated only by a few research groups, and important data about its role in normal and tumor cells is still missing. Even though its functions and structure are not yet fully understood, recent studies show that ELTD1 has a role in both physiological and pathological angiogenesis, and it appears to be a very important biomarker and a molecular target in cancer diseases. Upregulation of ELTD1 in malignant cells has been reported, and correlated with poor cancer prognosis. This review article aims to compile the existing data and to discuss the current knowledge on ELTD1 structure and signaling, and its role in physiological and neoplastic conditions.

show abstract

Modulation of CXCR4-Mediated Gi1 Activation by EGF Receptor and GRK2

Cited by 4 publications

References 34 publications

Phosphorylation of Gαi shapes canonical Gα(i)βγ/GPCR signaling

Phosphorylation of Gαi shapes canonical Gα(i)βγ/GPCR signaling

Crosstalk between CXCR4/ACKR3 and EGFR Signaling in Breast Cancer Cells

ELTD1—An Emerging Silent Actor in Cancer Drama Play

Contact Info

Product

Resources

About