The aim of this review is to describe the complex evolutionary processes that have integrated signaling cascades associated with 2 structurally and mechanistically dissimilar receptor families: G protein-coupled receptors (GPCRs) and membrane-spanning tyrosine kinase receptors (RTKs). Precision medicine, employing advanced personalized therapeutic strategies, requires better understanding of multiple mechanisms governing both normal and pathological cell regulation. The functional overlap of GPCRs and RTKs exhibits complex interactions. GPCRs canonically activate signaling through their interactions with G proteins; however, they can also initiate G protein-independent signaling through interactions with β-arrestin 1/2. In contrast to the GPCRs, RTK canonical signaling is initiated with ligand-dependent receptor kinase-mediated phosphorylation of specific intrinsic tyrosine substrates. This, in turn, activates multiple intracellular pathways. Despite these distinguishing characteristics, GPCRs and RTKs might have a common evolutionary origin. This shared ancestry potentially explains why GPCRs and RTKs can behave as functional RTK/GPCR hybrids by "borrowing" from each other's signaling toolbox. Intermingling of these cell surface receptors can result in noncanonical receptor transactivation/inactivation, trafficking, and signaling. Several mechanisms for heterogeneous receptor crosstalk have been proposed, including receptor protein/protein interactions and sharing docking, scaffolding, and downstream effectors. Recent identification of these signaling complexities has revealed unanticipated feedback loops and patterns of downstream target gene activation. In sum, recognizing these biological complexities should facilitate novel approaches to high-specificity therapeutic targeting.

Effect of β-arrestin imbalance on IGF1R expression

Background Inflammation in the eye is often associated with aggravated ocular diseases such as uveal melanoma (UM). Poor prognosis of UM is generally associated with high potential of metastatic liver dissemination. A strong driver of metastatic dissemination is the activation of the epithelial-mesenchymal transition (EMT) regulating transcription factor ZEB1, and high expression of ZEB1 is associated with aggressiveness of UM. While ZEB1 expression can be also associated with immune tolerance, the underlying drivers of ZEB1 activation remain unclear. Methods Transcriptomic, in vitro, ex vivo, and in vivo analyses were used to investigate the impact on clinical prognosis of immune infiltration in the ocular tumor microenvironment. A metastatic liver dissemination model of was developed to address the role of natural killer (NK) cells in driving the migration of UM. Results In a pan-cancer TCGA analysis, natural killer (NK) cells were associated with worse overall survival in uveal melanoma and more abundant in high-risk monosomy 3 tumors. Furthermore, uveal melanoma expressed high levels of the tumor necrosis factor superfamily member 4-1BB ligand, particularly in tumors with monosomy 3 and BAP1 mutations. Tumors expressing 4-1BB ligand induced CD73 expression on NK cells accompanied with the ability to promote tumor dissemination. Through ligation of 4-1BB, NK cells induced the expression of the ZEB1 transcription factor, leading to the formation of liver metastasis of uveal melanoma. Conclusions Taken together, the present study demonstrates a role of NK cells in the aggravation of uveal melanoma towards metastatic disease.

Effect of β-arrestin isoform imbalance on survival of patients with metastatic melanoma.

Table S2. Antibodies used in this study.

Effect of β-arrestin imbalance on response to dacarbazine (DTIC)

Metabolic profiles of breast cancer cells in response to estrogen treatment

EDITORIAL article Front. Endocrinol., 27 January 2023Sec. Cancer Endocrinology Volume 14 - 2023 | https://doi.org/10.3389/fendo.2023.1138326

Characterization of ERα cistromes for MCF7 and T47D cells

Increasing evidence suggests that the SYT-SSX fusion gene plays an important role in synovial sarcoma development and progression. However, very little is known about the downstream targets of SYT-SSX. In this study, we used antisense oligonucleotides to block the expression of the SYT-SSX fusion gene in synovial sarcoma cells. By comparing SYT-SSX inhibited cells with noninhibited cells, the gene expression profile was analysed using cDNA microarray and established by real-time PCR. Herewith, using a filter containing 1176 cancer-relevant genes, we found that the DNA repair gene XRCC4 and the DNA mismatch repair gene MSH2 were downregulated, whereas the gene encoding for the serine/threonine protein kinase PRK (also known as CNK), and the macrophage inhibitory cytokine MICI (also known as PLAB) were upregulated after the inhibition of SYT-SSX. In comparison, expression of the XRCC4 gene was undergoing the strongest alteration. Consistently, the protein expression of XRCC4 was found to be decreased after SYT-SSX inhibition, whereas there were no detectable changes for the other gene products. Our study provides some clues to elucidate the signaling pathways of the SYT-SSX fusion gene, as well as it demonstrates a valuable model system for search for other SYT-SSX targets.

Rescue-validation of β-arrestin imbalance effects on MDM2-dependent IGF1R expression.

Specificity of β-arrestin1/2 siRNA effectson MDM2 localization.

Changes of Cho-containing metabolites upon E2 stimulation

Supplementary Materials and Methods and Supplementary Figure and Table Legends

The core set of direct ERalpha regulated genes in breast cancer cells

Changed levels of intracellular metabolites in MCF7 and T47 D cells in response to estrogen

Association between CHPT1 expression in breast cancer samples and clinicopathological data.

Effect of combination treatment on p53-activation in skin melanoma malignant phenotype in in vitro 3D models