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Dopamine D2 receptor (D2R) has been shown to activate extracellular signal‐regulated kinases (ERKs) via distinct pathways dependent on either G‐protein or β‐arrestin. However, there has not been a systematic study of the regulatory process of D2R‐mediated ERKs activation by G protein‐ versus β‐arrestin‐dependent signaling since D2R stimulation of ERKs reflects the simultaneous action of both pathways. Here, we investigated that differential regulation of D2R‐mediated ERKs activation via these two pathways. Our results showed that G protein‐dependent ERKs activation was transient, rapid, reached maximum level at around 2 min, and importantly, the activated ERKs were entirely confined to the cytoplasm. In contrast, β‐arrestin‐dependent ERKs activation was more sustained, slower, reached maximum level at around 10 min, and phosphorylated ERKs translocated into the nucleus. Src was found to be commonly involved in both the G protein‐ and β‐arrestin‐dependent pathway‐mediated ERKs activation. Pertussis toxin Gi/o inhibitor, GRK2‐CT, AG1478 epidermal growth factor receptor inhibitor, and wortmannin phosphoinositide 3‐kinase inhibitor all blocked G protein‐dependent ERKs activation. In contrast, GRK2 and β‐Arr2 played a main role in β‐arrestin‐dependent ERKs activation. Receptor endocytosis showed minimal effect on the activation of ERKs mediated by both pathways. Furthermore, we found that the formation of a complex composed of phospho‐ERKs, β‐Arr2, and importinβ1 promoted the nuclear translocation of activated ERKs. The differential regulation of various cellular components, as well as temporal and spatial patterns of ERKs activation via these two pathways, suggest the existence of distinct physiological outcomes. [ABSTRACT FROM AUTHOR]

A class-A GPCR dopamine D2 receptor (D2R) plays a critical role in the proper functioning of neuronal circuits through the downstream activation of both G-protein- and β-arrestin-dependent signaling pathways. Understanding the signaling pathways downstream of D2R is critical for developing effective therapies with which to treat dopamine (DA)-related disorders such as Parkinson's disease and schizophrenia. Extensive studies have focused on the regulation of D2R-mediated extracellular-signal-regulated kinase (ERK) 1/2 signaling; however, the manner in which ERKs are activated upon the stimulation of a specific signaling pathway of D2R remains unclear. The present study conducted a variety of experimental techniques, including loss-of-function experiments, site-directed mutagenesis, and the determination of protein interactions, in order to investigate the mechanisms underlying β-arrestin-biased signaling-pathway-mediated ERK activation. We found that the stimulation of the D2R β-arrestin signaling pathway caused Mdm2, an E3 ubiquitin ligase, to move from the nucleus to the cytoplasm and interact with tyrosine phosphorylated G-protein-coupled receptor kinase 2 (GRK2), which was facilitated by Src, a non-receptor tyrosine kinase. This interaction led to the ubiquitination of GRK2, which then moved to the plasma membrane and interacted with activated D2R, followed by the phosphorylation of D2R as well as the mediation of ERK activation. In conclusion, Mdm2-mediated GRK2 ubiquitination, which is selectively triggered by the stimulation of the D2R β-arrestin signaling pathway, is necessary for GRK2 membrane translocation and its interaction with D2R, which in turn mediates downstream ERK signaling. This study is primarily novel and provides essential information with which to better understand the detailed mechanisms of D2R-dependent signaling. [ABSTRACT FROM AUTHOR]

Purpose: The study aims at examining the relationship between market-orientation, organisational learning and internal market-orientation. Research Methodology: It is based on the responses obtained from managers of four public-sector banks operating in north India. The statistical tools of confirmatory factor analysis and structural equation modeling were used for data analysis. Results: The study reveals that market-orientation is significantly related to both organisational learning and internal market-orientation. Moreover, organisational learning plays a mediating role in the relationship between market-orientation and internal market-orientation. Limitation: It is limited to one sector of the economy, viz., banking, which implies that its findings may not be generalised for the other sectors. Originality/Value: The originality of the study lies in its contribution to the existing research through an analysis of the relationship between strategic marketing practices, especially, market-orientation, organisational learning, and internal market-orientation. Policy Implications: Its findings imply that developing and supporting a learning culture in an organisation is essential for transmitting the influence of market-orientation on internal market-orientation. [ABSTRACT FROM AUTHOR]

Dopamine D 2 receptor (D 2 R) has been shown to activate extracellular signal-regulated kinases (ERKs) via distinct pathways dependent on either G-protein or β-arrestin. However, there has not been a systematic study of the regulatory process of D 2 R-mediated ERKs activation by G protein- versus β-arrestin-dependent signaling since D 2 R stimulation of ERKs reflects the simultaneous action of both pathways. Here, we investigated that differential regulation of D 2 R-mediated ERKs activation via these two pathways. Our results showed that G protein-dependent ERKs activation was transient, rapid, reached maximum level at around 2 min, and importantly, the activated ERKs were entirely confined to the cytoplasm. In contrast, β-arrestin-dependent ERKs activation was more sustained, slower, reached maximum level at around 10 min, and phosphorylated ERKs translocated into the nucleus. Src was found to be commonly involved in both the G protein- and β-arrestin-dependent pathway-mediated ERKs activation. Pertussis toxin Gi/o inhibitor, GRK2-CT, AG1478 epidermal growth factor receptor inhibitor, and wortmannin phosphoinositide 3-kinase inhibitor all blocked G protein-dependent ERKs activation. In contrast, GRK2 and β-Arr2 played a main role in β-arrestin-dependent ERKs activation. Receptor endocytosis showed minimal effect on the activation of ERKs mediated by both pathways. Furthermore, we found that the formation of a complex composed of phospho-ERKs, β-Arr2, and importinβ1 promoted the nuclear translocation of activated ERKs. The differential regulation of various cellular components, as well as temporal and spatial patterns of ERKs activation via these two pathways, suggest the existence of distinct physiological outcomes., (© 2023 Federation of European Biochemical Societies.)

Over the years, we have made considerable progress in our understanding of the biology of various cancers leading to advancements in their management strategies. Consequently, we have witnessed steady improvements in survival rates of cancer patients post-diagnosis. The progress; however, has been slow for some cancer types and the advances in cancer care have not benefited all the communities equally in the United States. The state of Alabama has one of the most diverse demographics in the country and as a result, we witness significant health disparities among our populations. Breast and cervical cancers are the two major cancer types that disparately affect the women in our state. Here, we describe the extent of disparities in the diagnosis and death rates from these cancers in the state of Alabama and discuss potential underlying causes affecting the health outcomes. We also discuss ongoing efforts undertaken to reduce the disparity gaps and provide a perspective for addressing these disparities more effectively., Competing Interests: Conflict of interest The authors declare that they have no conflict of interest.