G Protein-Coupled Receptor Signaling: Implications and Therapeutic Development Advances in Cancers

Abstract

G protein-coupled receptors (GPCRs) are the largest and most diverse class of membrane proteins, mediating cellular responses to a wide range of extracellular stimuli. GPCRs initiate complex intracellular signaling networks that regulate vital physiological functions and are associated with numerous diseases, including various types of cancer. Their conserved seven-transmembrane (7TM) structure enables these signaling networks by allowing interactions with multiple ligands and intracellular effectors. In several types of tumors, abnormal GPCR signaling promotes carcinogenesis by supporting immune evasion, cell proliferation, and therapeutic resistance. A significant research gap exists in fully understanding the molecular mechanisms behind pathway-specific activation and biased ligand discovery of GPCRs, which could lead to the development of more effective therapies. This review examines the complexity of GPCRs, with a focus on their role in signaling through the differential activation of pathways regulated by β-arrestin and G proteins. It discusses how targeted modulation of signaling outcomes by receptor mutants might offer therapeutic benefits in cancer treatment. The review also highlights emerging technologies, such as aptamers, PROTACs, and nanobodies, that more precisely target GPCRs. In addition to exploring receptor structure-function relationships and pathway selectivity, this review provides valuable insights into GPCR-biased signaling and its implications in cancer biology.

Keywords: GPCRs; bias; cancer; diseases; signaling; therapeutics.

FIGURE 1

Diverse classes of GPCRs and their role in disease progression. This figure illustrates the classification of GPCRs and their critical roles in disease mechanisms. It emphasizes the relationship between ligand binding and the activation of specific signaling pathways, showcasing how each GPCR class uniquely contributes to pathological processes. The visual highlights the complexity of GPCR‐mediated responses and their significance as potential therapeutic targets, focusing on the interplay between ligand specificity and signaling diversity in various conditions. Abbreviations: GPCR—G protein‐coupled receptor, TSHR—thyroid‐stimulating hormone receptor, FSHR—follicle‐stimulating hormone receptor, CB1—cannabinoid receptor type 1, CB2—cannabinoid receptor type 2, MT1—melatonin receptor 1, MT2—melatonin receptor 2, ADGRB3—adhesion G protein‐coupled receptor B3, ADGRL3—adhesion G protein‐coupled receptor L3, GABA—gamma‐aminobutyric acid, mGluRs—metabotropic glutamate receptors, CaSR—calcium‐sensing receptor, SMO—smoothened receptor, FZ—frizzled receptor.

FIGURE 2

Distinct signaling branches of Gα proteins in GPCR pathways. The figure depicts the distinct signaling branches of Gαs, Gαq, and Gαi. This visual representation underscores the signaling associated with physiological impacts. Each branch highlights the subtle interplay between receptor activation and downstream effects. Understanding these signaling dynamics is crucial for harnessing GPCRs in therapeutic applications. Abbreviations: Gαs—stimulatory G protein alpha subunit, Gαi—inhibitory G protein alpha subunit, Gαq—G protein alpha q subunit, cAMP—cyclic adenosine monophosphate, PKA—protein kinase A, CREB—cAMP response element‐binding protein, PLC—phospholipase C, PIP2—phosphatidylinositol 4,5‐bisphosphate, DAG—diacylglycerol, IP3—inositol trisphosphate, NFAT—nuclear factor of activated T‐cells.

FIGURE 3

Roles of G proteins and GPCRs in cancer progression. Key G proteins and G protein‐coupled receptors (GPCRs) are highlighted as drivers of hallmark traits in cancer. Dysregulated signaling through these receptors supports tumor growth and progression by altering cellular processes and oncocrine networks within the tumor microenvironment. Abbreviations: GNAQ—G protein subunit alpha q, GNAS—G protein subunit alpha s, GNA12—G protein subunit alpha 12, GNA13—G protein subunit alpha 13, GNAI2—G protein subunit alpha i2, CXCR4—C‐X‐C chemokine receptor type 4, FZ7—frizzled class receptor 7, PAR1—protease‐activated receptor 1, VIPR2—vasoactive intestinal peptide receptor 2, P2Y2—purinergic receptor P2Y2, GPR68—G protein‐coupled receptor 68, LPAR1—lysophosphatidic acid receptor 1.

FIGURE 4

Wnt/β‐catenin pathway and dysregulation of GPCR signaling in cancer. (A) The Wnt/β‐catenin pathway is characteristic of the Frizzled (FZ) class F GPCRs, stimulated by Wnt (Wingless/Int1) proteins and activating G protein‐independent (DVL) and G protein‐dependent pathways. The canonical Wnt pathway activates β‐catenin signaling by binding Wnt to the Fz and LRP5/6 receptors. Without Wnt, β‐catenin is degraded by the “degradation complex.” Wnt binding disrupts this complex, stabilizing β‐catenin, facilitating its nuclear translocation, and promoting transcriptional activation via Lef/Tcf factors. Noncanonical Wnt signaling (e.g., Wnt5a) is mediated via Fz, affecting, among others, the activation of JNK and the cytoskeleton. (B) GPCR dysregulation in cancer is illustrated, showing its contribution to cancer hallmarks, including uncontrolled proliferation, evasion of apoptosis, and metastasis. Abbreviations: GSK3β—glycogen synthase kinase 3 beta, TCF/LEF—T‐cell factor/lymphoid enhancer‐binding factor, JNK—c‐Jun N‐terminal kinase, NF‐κB—nuclear factor kappa B, mTOR—mechanistic target of rapamycin, MAPK—mitogen‐activated protein kinase, ERK—extracellular signal‐regulated kinase, ROCK—Rho‐associated coiled‐coil containing protein kinase, RhoA—Ras homolog family member A, FAK—focal adhesion kinase, Src—proto‐oncogene tyrosine‐protein kinase Src, YAP—Yes‐associated protein, P38—p38 mitogen‐activated protein kinase.

FIGURE 5

Key GPCR‐associated pathways in tumorigenesis. (A) Hippo signaling pathway: LATS1/2 kinases phosphorylate YAP/TAZ, thereby inactivating them and restricting their nuclear entry. Gαs activates Hippo (inhibiting YAP/TAZ), while Gα12/13, Gαi, and Gαq/11 activate YAP/TAZ, promoting tumorigenesis. (B) Hedgehog pathway: In the absence of Hh, PTCH inhibits SMO, thereby blocking GLI activation. When Hh binds to PTCH, SMO is activated, leading to the activation of Gαi signaling and, in turn, activating GLI‐driven transcription that promotes tumor growth. (C) β‐arrestin‐mediated signaling: β‐arrestins (β‐arr1, β‐arr2) modulate GPCR desensitization by inhibiting G proteins while activating G protein‐independent pathways. These include ERK1/2, PI3K/AKT, and Hedgehog signaling, which are critical for cancer progression. This panel highlights the dual role of β‐arrestins in regulating GPCR signaling and promoting tumor growth and metastasis. Abbreviations: MST1/2—mammalian sterile 20‐like kinase 1 and 2, LATS1/2—large tumor suppressor kinase 1 and 2, YAP—Yes‐associated protein, TAZ—transcriptional coactivator with PDZ‐binding motif, TEAD1—TEA domain transcription factor 1, SHh—sonic hedgehog, PTCH—patched receptor, GLI—glioma‐associated oncogene homolog, VEGF—vascular endothelial growth factor, CXCL8—C‐X‐C motif chemokine ligand 8.