G protein-coupled receptors (GPCRs) mediate signal transduction via G protein or β-arrestin. Several biased ligands and receptors that preferentially signal through either G protein- or β-arrestin-mediated pathways have been identified. These discoveries have redefined the classical GPCR signaling paradigm. Distinct ligand-receptor binding sites might be one of the main reasons for biased signal transduction. It is posited that multiple active conformations of receptors lead to distinct kinase phosphorylation patterns on C terminus of receptors. Phosphorylation patterns decide which signal pathway will be transduced. The biased signal pathway transduction has been found in more than 40 GPCRs till now. A few of them have been found involved in fine-regulation of physiological processes. However, most others still need further investigation. The biased ligands may be developed as tools for understanding the basic physiology of GPCR, and, potentially and most importantly, as fine-tuned therapeutics that maximize beneficial effects and minimize adverse or unwanted effects. These studies will provide new insights into new drug discovery.
Ligands ; Phosphorylation ; Receptors, G-Protein-Coupled ; Signal Transduction

Prostate cancer (PCa) exhibits epidemiological and molecular heterogeneity. Despite extensive studies of its phenotypic and genetic properties in Western populations, its molecular basis is not clear in Chinese patients. To determine critical molecular characteristics and explore correlations between genomic markers and clinical parameters in Chinese populations, we applied an integrative genetic/transcriptomic assay that combines targeted next-generation sequencing and quantitative real-time PCR (qRT-PCR) on samples from 46 Chinese patients with PCa. Lysine (K)-specific methyltransferase 2D (KMT2D), zinc finger homeobox 3 (ZFHX3), A-kinase anchoring protein 9 (AKAP9), and GLI family zinc finger 1 (GLI1) were frequently mutated in our cohort. Moreover, a clinicopathological analysis showed that RB transcriptional corepressor 1 (RB1) deletion was common in patients with a high risk of disease progression. Remarkably, four genomic events, MYC proto-oncogene (MYC) amplification, RB1 deletion, APC regulator of WNT signaling pathway (APC) mutation or deletion, and cyclin-dependent kinase 12 (CDK12) mutation, were correlated with poor disease-free survival. In addition, a close link between KMT2D expression and the androgen receptor (AR) signaling pathway was observed both in our cohort and in The Cancer Genome Atlas Prostate Adenocarcinoma (TCGA-PRAD) data. In summary, our results demonstrate the feasibility and benefits of integrative molecular characterization of PCa samples in disease pathology research and personalized medicine.
A Kinase Anchor Proteins/genetics* ; Adult ; Aged ; Biomarkers, Tumor/genetics* ; China ; Cytoskeletal Proteins/genetics* ; DNA-Binding Proteins/genetics* ; Gene Amplification ; High-Throughput Nucleotide Sequencing ; Homeodomain Proteins/genetics* ; Humans ; Male ; Middle Aged ; Mutation ; Neoplasm Proteins/genetics* ; Prostatic Neoplasms/pathology* ; Proto-Oncogene Mas ; Receptors, Androgen/genetics* ; Signal Transduction/genetics* ; Zinc Finger Protein GLI1/genetics*