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Modulation of CXCR4-Mediated Gi1 Activation by EGF Receptor and GRK2
journal contribution
posted on 2020-05-01, 15:13 authored by Maria Neves, Cristina Perpiñá-Viciano, Petronila Penela, Carsten Hoffmann, Federico MayorThe CXCL12 chemokine
receptor CXCR4 belongs to the GPCR superfamily
and is often overexpressed in cancer, being involved in tumor progression
and metastasis. How CXCR4 signaling integrates with other relevant
oncogenic transduction pathways and the role of GPCR regulatory mechanisms
in such contexts are not well-understood. Recent data indicate concurrent
upregulation in certain tumors of CXCR4, EGF receptor (EGFR), and
G protein-coupled receptor kinase 2 (GRK2), a signaling node functionally
linked to both receptor types. We have investigated in a model system
the effect of the EGFR and GRK2 status on CXCL12/CXCR4-mediated activation
of Gi, the earliest step downstream of receptor activation. We find
that overexpressed and activated EGFR reduces CXCR4-mediated Gi1 activation
and that GRK2 phosphorylation at tyrosine residues is required to
exert its inhibitory actions on CXCR4–Gi stimulation, suggesting
a shared path of modulation. Our data point to a role for GRK2 in
the crosstalk of the CXCR4 and EGFR signal transduction pathways in
pathological contexts characterized by concurrent overactivation of
these proteins.