G-Protein–Coupled Receptor Kinase 2 as a Potential Modulator of the Hallmarks of Cancer

Abstract

Malignant features-such as sustained proliferation, refractoriness to growth suppressors, resistance to cell death or aberrant motility, and metastasis-can be triggered by a variety of mutations and signaling adaptations. Signaling nodes can act as cancer-associated factors by cooperating with oncogene-governed pathways or participating in compensatory transduction networks to strengthen tumor properties. G-protein-coupled receptor kinase 2 (GRK2) is arising as one of such nodes. Via its complex network of connections with other cellular proteins, GRK2 contributes to the modulation of basic cellular functions-such as cell proliferation, survival, or motility-and is involved in metabolic homeostasis, inflammation, or angiogenic processes. Moreover, altered GRK2 levels are starting to be reported in different tumoral contexts and shown to promote breast tumorigenesis or to trigger the tumoral angiogenic switch. The ability to modulate several of the hallmarks of cancer puts forward GRK2 as an oncomodifier, able to modulate carcinogenesis in a cell-type specific way.

GRK2 suppresses lymphomagenesis by inhibiting the MALT1 proto-oncoprotein

“…GRK2 is emerging as an important "oncomodulator," a protein that influences multiple cellular functions related to the hallmarks of cancer, such as cell proliferation, cell survival, cell motility, cell metabolism, and angiogenesis, via its impact on cancer-relevant signaling networks (38). Many recent studies show recently been extended beyond B cell lymphoma to include T cell malignancy.…”

“…GRK2 has been reported to influence tumor progression in several different cancers, and the specific mechanism by which GRK2 exerts its influence depends on the tumor cell type. For example, it has been reported that GRK2 promotes the growth of certain breast cancers via phosphorylation and activation of histone deacetylase 6 (HDAC6) (38,75). As another example, 2 recent reports suggest that GRK2 is overexpressed in pancreatic cancer and may serve as an indicator of unfavorable prognosis (76,77).…”

“…Emerging evidence indicates that in addition to this canonical function, GRK2 binds to a variety of other cellular proteins involved in diverse aspects of signal transduction, and regulates the activity of these signaling proteins via kinase-independent mechanisms (37). While GRK2 has been reported to influence many of the processes involved in the hallmarks of cancer, such as cell proliferation, survival, motility metabolism, and others, the role of GRK2 in tumor formation and progression has only recently begun to be investigated (38). GRK2 is expressed in several cell types within the immune system, though relatively little is known about the function of GRK2 in either normal or malignant lymphocytes (39).…”

CD97 Promotes Tumor Aggressiveness Through the Traditional G Protein–Coupled Receptor–Mediated Signaling in Hepatocellular Carcinoma

“…GRKs phosphorylate specific residues in the cytoplasmic domains of activated GPCRs, which is a critical step for the recruitment and binding of arrestins. GRKs modulate the responses to many GPCRs involved in tumor signaling and act as hubs regulating several cellular processes related to cancer progression through interactions with other components of the signal‐transduction cascades . Recent studies have shown that GRK6 deficiency promotes tumor metastasis through consequent up‐regulation of metastasis‐mediating matrix metalloproteinases (MMPs) …”

“…GRKs modulate the responses to many GPCRs involved in tumor signaling and act as hubs regulating several cellular processes related to cancer progression through interactions with other components of the signal-transduction cascades. (26,27) Recent studies have shown that GRK6 deficiency promotes tumor metastasis through consequent up-regulation of metastasis-mediating matrix metalloproteinases (MMPs). (28) In the current study, we demonstrate that CD97 promotes HCC metastasis.…”