G protein-coupled receptor kinases (GRKs) in tumorigenesis and cancer progression: GPCR regulators and signaling hubs

Nogués, Laura; Palacios‐García, Julia; Reglero, Clara; Rivas, Verónica; Neves, Maria G. P. M. S.; Ribas, Catalina; Penela, Petronila; Mayor, Federico

doi:10.1016/j.semcancer.2017.04.013

Cited by 76 publications

(69 citation statements)

References 115 publications

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“…A recent study using single‐molecule fluorescence microscopy to visualize in real time the internalization of GPCR supports our conclusions with respect to the function of ligand stimulation . Changes in GPCR expression or functionality may trigger tumor progression through β ‐arrestin‐dependent receptor cascades . GPCR and β ‐arrestin interactions have been verified based on the structure of the human rhodopsin/mouse S‐arrestin (protein databank, 4ZWJ) fusion protein complex .…”

Section: Discussionsupporting

confidence: 79%

“…(32) Changes in GPCR expression or functionality may trigger tumor progression through β-arrestin-dependent receptor cascades. (33)(34)(35) GPCR and β-arrestin interactions have been verified based on the structure of the human rhodopsin/ mouse S-arrestin (protein databank, 4ZWJ) fusion protein complex. (25) Zhou et al (23) reported an X-rayfree electron laser crystal structure of the rhodopsinarrestin complex.…”

Section: Discussionmentioning

confidence: 99%

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

Yin

Tang

et al. 2018

Hepatology

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Cluster of differentiation 97 (CD97) is a member of the epidermal growth factor seven-transmembrane family belonging to the class B G protein-coupled receptors (GPCRs). The protein affects tumor aggressiveness through its cellular ligand CD55 stimulation and exhibits adhesive properties. Studies have demonstrated the involvement of CD97 in dedifferentiation, migration, invasiveness, and metastasis of tumors. However, little information is currently available on the specific role of CD97 in hepatocellular carcinoma (HCC). Here, we have shown that CD97 up-regulation in HCCs is positively correlated with tumor metastasis. Functionally, CD97 promoted cell migration and invasion in vitro. In an in vivo mouse model, overexpression of CD97 in HCC cells led to accelerated lung metastasis. Mechanistically, CD97 cooperated with the altered regulator, GPCR kinase 6 (GRK6), to mediate GPCR desensitization and internalization. Down-regulation of GRK6 suppressed CD97 internalization and promoted CD97 expression. Integrated regulatory interactions between CD97 and GRK6 stimulated downstream matrix metalloproteinase 2/9 secretion and, consequently, HCC metastasis. Conclusion: Our collective findings support the utility of CD97 as an effective potential prognosticator and therapeutic target for HCC.

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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

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

Yin

Tang

et al. 2018

Hepatology

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“…GPCR activity is a result of a tightly regulated balance between activation, desensitization, and resensitization events. After receptor activation and interaction with G proteins, several mechanisms integrate to trigger GPCR desensitization and/or modulate additional signaling cascades, including phosphorylation by GRKs and recruitment of b-arrestins (Penela et al, 2010b;Nogués et al, 2018).…”

Section: Association Of Cxcr4 and Ackr3 With Canonical Gpcr-interactimentioning

confidence: 99%

“…Altered GRK expression/activity can also impair CXCR4 phosphorylation patterns. GRK3 suppression may contribute to abnormally sustained CXCR4 signaling in classic types of glioblastoma (Woerner et al, 2012), some WHIM patients (Balabanian et al, 2008), and in triple negative breast cancer, thus potentiating CXCR4-dependent migration, invasion, and metastasis (Billard et al, 2016;Nogués et al, 2018). It is interesting to note that, although GRKs 2 and 3 share a high homology and are able to phosphorylate the same residues in CXCR4 in model cells, their function is not redundant.…”

Section: Downloaded Frommentioning

confidence: 99%

CXCR4/ACKR3 Phosphorylation and Recruitment of Interacting Proteins: Key Mechanisms Regulating Their Functional Status

et al. 2019

Self Cite

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The C-X-C motif chemokine receptor type 4 (CXCR4) and the atypical chemokine receptor 3 (ACKR3/CXCR7) are class A G protein-coupled receptors (GPCRs). Accumulating evidence indicates that GPCR subcellular localization, trafficking, transduction properties, and ultimately their pathophysiological functions are regulated by both interacting proteins and post-translational modifications. This has encouraged the development of novel techniques to characterize the GPCR interactome and to identify residues subjected to post-translational modifications, with a special focus on phosphorylation. This review first describes state-of-the-art methods for the identification of GPCR-interacting proteins and GPCR phosphorylated sites. In addition, we provide an overview of the current knowledge of CXCR4 and ACKR3 post-translational modifications and an exhaustive list of previously identified CXCR4-or ACKR3-interacting proteins. We then describe studies highlighting the importance of the reciprocal influence of CXCR4/ACKR3 interactomes and phosphorylation states. We also discuss their impact on the functional status of each receptor. These studies suggest that deeper knowledge of the CXCR4/ACKR3 interactomes along with their phosphorylation and ubiquitination status would shed new light on their regulation and pathophysiological functions.

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“…Thus, the effects of GRK2 on heart function seem to depend both on its expression level and on pathophysiological context. Moreover, altered GRK2 levels and functionality have been found in patient samples and/or in animal models of relevant pathological situations such as HF, hypertension, obesity and insulin resistance‐related situations, nonalcoholic fatty liver disease, pain, inflammation, and some types of cancer, where anomalous GRK2 dosage or activity appears to contribute to disease progression via cell type and context‐specific molecular mechanisms (Cannavo et al, ; Cruces‐Sande et al, ; Gurevich, Gainetdinov, & Gurevich, ; Hullmann, Traynham, Coleman, & Koch, ; Mayor Jr. et al, ; Mushegian, Gurevich, & Gurevich, ; Nogues et al, ; Penela, Nogues, & Mayor Jr., ; Wang, Gu, Eijkelkamp, Heijnen, & Kavelaars, ).…”

Section: Involvement Of G‐protein‐coupled Receptor Kinase (Grk) Signamentioning

confidence: 99%

Molecular signaling of G‐protein‐coupled receptor in chronic heart failure and associated complications

Altamish

Samuel

Dahiya

et al. 2019

Drug Development Research

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The well‐known condition of heart failure is a clinical syndrome that results when the myocardium's ability to pump enough blood to meet the body's metabolic needs is impaired. Most of the cardiac activity is maintained by adrenoceptors, are categorized into two main α and β and three distinct subtypes of β receptor: β1‐, β2‐, and β3‐adrenoceptors. The β adrenoreceptor is the main regulatory macro proteins, predominantly available on heart and responsible for down regulatory cardiac signaling. Moreover, the pathological involvement of Angiotensin‐converting enzyme 1 (ACE1)/angiotensin II (Ang II)/angiotensin II type 1 (AT1) axis and beneficial ACE2/Ang (1‐7)/Mas receptor axis also shows protective role via Gi βγ, during heart failure these receptors get desensitized or internalized due to increase in the activity of G‐protein‐coupled receptor kinase 2 (GRK2) and GRK5, responsible for phosphorylation of G‐protein‐mediated down regulatory signaling. Here, we investigate the various clinical and preclinical data that exhibit the molecular mechanism of upset level of GRK change the cardiac activity during failing heart.

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G protein-coupled receptor kinases (GRKs) in tumorigenesis and cancer progression: GPCR regulators and signaling hubs

Cited by 76 publications

References 115 publications

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

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

CXCR4/ACKR3 Phosphorylation and Recruitment of Interacting Proteins: Key Mechanisms Regulating Their Functional Status

Molecular signaling of G‐protein‐coupled receptor in chronic heart failure and associated complications

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