G Protein–Coupled Receptor Kinase 6 Deficiency Promotes Angiogenesis, Tumor Progression, and Metastasis

Abstract

G protein coupled receptor kinases (GRKs) phosphorylate the activated form of G protein coupled receptors (GPCRs) leading to receptor desensitization and down-regulation. We have recently shown that the chemokine receptor, CXCR2, couples to GRK6 to regulate cellular responses including chemotaxis, angiogenesis and wound healing. In this study, we investigate the role of GRK6 in tumorigenesis using murine models of human lung cancer. Mice deficient in GRK6 (GRK6−/−) exhibited a significant increase in Lewis lung cancer (LLC) growth and metastasis relative to control littermates (GRK6+/+). GRK6 deletion had no effect on the expression of proangiogenic chemokine or vascular endothelial growth factor (VEGF), but up-regulated matrix metalloproteinase (MMP)-2 and MMP-9 release, tumor-infiltrating PMNs and microvessel density. Since βarr2−/− mice exhibited increase LLC growth and metastasis similar to that of GRK6−/−we developed a double GRK6−/−/βarr2−/− mouse model. Surprisingly, GRK6−/−/βarr2−/− mice exhibited faster tumor growth relative to GRK6−/− or βarr2−/− mice. Treatment of the mice with anti-CXCR2 antibody inhibited tumor growth in both GRK6−/− and GRK6−/−/βarr2−/− animals. Altogether, the results indicate that CXCR2 couples to GRK6 to regulate angiogenesis, tumor progression and metastasis. Deletion of GRK6 increases the activity of the host CXCR2, resulting in greater PMN infiltration and MMP release in the tumor microenvironment thereby promoting angiogenesis and metastasis. Since GRK6−/−/βarr2−/− showed greater tumor growth relative to GRK6−/− or βarr2−/− mice, the data further suggest that CXCR2 couples to different mechanisms to mediate tumor progression and metastasis.

Role of G protein-coupled receptor kinases in cell migration

“…In epithelial cells, a functional screening identified GRK6 as a critical mediator in integrin-mediated cell adhesion and migration of tumor cells [35], and GRK6 deficiency reportedly promotes CXCR2 receptor-mediated tumor progression and metastasis in a lung carcinoma model [36]. It would be interesting to investigate whether the modulation of cell migration by these GRKs is mostly related to their canonical role as specific or more active regulators of given GPCRs in different cell types or novel substrates and interactors as those identified for GRK2 are also targeted.…”

Overexpression of GRK6 associates with the progression and prognosis of colorectal carcinoma

“…GRK6 is the most recently identified member of the family of GRKs (10). Recent studies demonstrated that the overexpression of GRK6 exerts an important role in the process of transduction of pain signals (11,(28)(29)(30)(31). Previous studies also revealed that endogenous GRK6 molecules contribute to the desensitization of M3 muscarinic acetylcholine in the human SH-SY5Y neuroblastoma cell line (32).…”

“…levels in CRC. Previous studies have revealed that GRK6 expression contributes to the progression of several types of cancer (11,16,18,(28)(29)(30)(31). Despite these diverse studies, the precise functions and the mechanistic actions of GRK6 have not been defined completely.…”

“…GRKs promote the receptor-arrestin interaction and the uncoupling of the receptor from its G protein by phosphorylating specific serine and threonine residues in the cytoplasmic domains of the activated receptor (10,11). GRK6 is the most recently identified member of the family of GRKs (10).…”

“…GRKs promote the receptor-arrestin interaction and the uncoupling of the receptor from its G protein, by phosphorylating specific serine and threonine residues in the cytoplasmic domains of the activated receptor (10,11). Despite the critical role of GRKs in homologous desensitization, aberrant GRK activity has been identified in cases of opiate addiction, heart failure, and tumor progression and metastasis (12)(13)(14).…”