The ubiquitination status of the glucagon receptor determines signal bias.

The pancreatic hormone glucagon activates the glucagon receptor (GCGR), a class B seven-transmembrane G protein-coupled receptor that couples to the stimulatory heterotrimeric G protein and provokes PKA-dependent signaling cascades vital to hepatic glucose metabolism and islet insulin secretion. Glucagon-stimulation also initiates recruitment of the endocytic adaptors, ßarrestin1 and ßarrestin2, which regulate desensitization and internalization of the GCGR. Unlike many other G protein-coupled receptors, the GCGR expressed at the plasma membrane is constitutively ubiquitinated and upon agonist-activation, internalized GCGRs are deubiquitinated at early endosomes and recycled via Rab4-containing vesicles. Herein we report a novel link between the ubiquitination status and signal transduction mechanism of the GCGR. In the deubiquitinated state, coupling of the GCGR to Gs is diminished, while binding to ßarrestin is enhanced with signaling biased to a ßarrestin1-dependent p38 mitogen activated protein kinase (MAPK) pathway. This ubiquitin-dependent signaling bias arises through the modification of lysine333 (K333) on the cytoplasmic face of transmembrane helix V. Compared with the GCGR-WT, the mutant GCGR-K333R has impaired ubiquitination, diminished G protein coupling, and PKA signaling but unimpaired potentiation of glucose-stimulated-insulin secretion in response to agonist-stimulation, which involves p38 MAPK signaling. Both WT and GCGR-K333R promote the formation of glucagon-induced ßarrestin1-dependent p38 signaling scaffold that requires canonical upstream MAPK-Kinase3, but is independent of Gs, Gi, and ßarrestin2. Thus, ubiquitination/deubiquitination at K333 in the GCGR defines the activation of distinct transducers with the potential to influence various facets of glucagon signaling in health and disease.

Cancer Mortality in U.S.-Born versus Foreign-Born Asian American Groups (2008-2017).

BACKGROUND: Asian Americans (AA) are the fastest growing ethnic group in the United States with high proportions of immigrants. Nativity is important as cancer risk factors vary by country. We sought to understand differences in cancer mortality among AAs by nativity (foreign-born vs. U.S.-born). METHODS: Ninety-eight thousand eight hundred and twenty-six AA (Asian Indian, Chinese, Filipino, Japanese, Korean, Vietnamese) decedents with cancer-related deaths from U.S. death certificates (2008-2017) were analyzed. Thirteen cancers that contribute significantly to Asian-American cancer mortality were selected and categorized by etiology: tobacco-related, screen-detected, diet-/obesity-related, and infection-related. Ten-year age-adjusted mortality rates [AAMR; 95% confidence interval (CI); per 100,00] and standardized mortality ratios (SMR; 95% CI) using foreign-born as the reference group were calculated. RESULTS: Overall, foreign-born AAs had higher mortality rates than U.S.-born. Japanese U.S.-born males had the highest tobacco-related mortality rates [foreign-born AAMR: 43.02 (38.72, 47.31); U.S.-born AAMR: 55.38 (53.05, 57.72)]. Screen-detected death rates were higher for foreign-born than U.S.-born, except for among Japanese males [SMR 1.28 (1.21-1.35)]. Diet-/obesity-related AAMRs were higher among females than males and highest among foreign-born females. Foreign-born males and females had higher infection-related AAMRs than U.S.-born; the highest rates were foreign-born males-Korean [AAMR 41.54 (39.54, 43.53)] and Vietnamese [AAMR 41.39 (39.68, 43.09)]. CONCLUSIONS: We observed substantial heterogeneity in mortality rates across AA groups and by nativity. Contrary to the Healthy Immigrant Effect, most foreign-born Asians were dying at higher rates than U.S.-born AAs. IMPACT: Disaggregated analysis of AA cancers, targeted and culturally tailored cancer screening, and treatments for infections among foreign-born Asians is critical for cancer prevention efforts.