Post-translational modification (PTM) has a significant impact on cellular signaling and function regulation. In pancreatic β cells, PTMs are involved in insulin secretion, cell development, and viability. The dysregulation of PTM in β cells is clinically associated with the development of diabetes mellitus. Here, we summarized current findings on major PTMs occurring in β cells and their roles in insulin secretion. Our work provides comprehensive insight into understanding the mechanisms of insulin secretion and potential therapeutic targets for diabetes from the perspective of protein PTMs.

Studies showed that SARS-CoV-2 can directly target the kidney and induce renal damage. As the cell surface receptor for SARS-CoV-2 infection, the angiotensin-converting enzyme 2 (ACE2) plays a pivotal role for renal physiology and function. Thus, it is important to understand ACE2 through which pathway influences the pathogenesis of renal damage induced by COVID-19. In this study, we first performed an eQTL mapping for Ace2 in kidney tissues in 53 BXD mice strains. Results demonstrated that Ace2 is highly expressed and strongly controlled by a genetic locus on chromosome 16 in the kidney, with six genes ( Dnase1 , Vasn , Usp7 , Abat , Mgrn1 , and Rbfox1 ) dominated as the upstream modulator, as they are highly correlated with Ace2 expression. Gene co-expression analysis showed that Ace2 co-variates are significantly involved in the renin-angiotensin system (RAS) pathway which acts as a reno-protector. Importantly, we also found that Ace2 is positively correlated with Pdgf family members, particularly Pdgfc , which showed the most association among the 76 investigated growth factors. Mammalian Phenotype Ontology enrichment indicated that the cognate transcripts for both Ace2 and Pdgfc were mainly involved in regulating renal physiology and morphology. Among which, Cd44 , Egfr , Met , Smad3 , and Stat3 were identified as hub genes through protein–protein interaction analysis. Finally, in aligning with our systems genetics findings, we found ACE2 , pdgf family members, and RAS genes decreased significantly in the CAKI-1 kidney cancer cells treated with S protein and receptor binding domain structural protein. Collectively, our data suggested that ACE2 work with RAS, PDGFC, as well as their cognate hub genes to regulate renal function, which could guide for future clinical prevention and targeted treatment for COVID-19–induced renal damage outcomes. Key messages • Ace2 is highly expressed and strongly controlled by a genetic locus on chromosome 16 in the kidney. • Ace2 co-variates are enriched in the RAS pathway. • Ace2 is strongly correlated with the growth factor Pdgfc. • Ace2 and Pdgfc co-expressed genes involved in the regulation of renal physiology and morphology. • SARS-CoV-2 spike glycoprotein induces down-regulation of Ace2, RAS, and Pdgfc. Supplementary Information ...

It has been reported that c-Met and TRK synergistically promote multiple tumour progression, and therefore blocking the cross-signalling pathway between them may inhibit the growth of multiple tumours. In this study, we developed a tyrosine kinase inhibitor 1D228, which exhibited great anti-tumor activity by targeting TRK and c-Met. In the in vitro models, 1D228 showed a significant better inhibition on cancer cell proliferation and migration than the similar drug tepotinib. In the in vivo tumor models, 1D228 showed robust anti-tumor effect on gastric (TGI, 1D228-8 mg/kg/d: 94.8%; tepotinib 8mg/kg/d: 67.61%) and liver (TGI, 1D228-4 mg/kg/d: 93.4%; tepotinib 4mg/kg/d: 63.9%) tumor growth. Importantly, compared with the combination of larotrectinib and tepotinib, 1D228 monotherapy showed stronger antitumor activity and lower toxicity. Mechanistic studies showed that 1D228 can largely inhibit the phosphorylation of TRK and c-Met, thereby blocking downstream signaling pathways of TRK and c-Met. Interestingly, both kinases can be co-expressed at high levels in patients with gastric cancer. Cell cycle analysis found that 1D228 induced G0/G1 arrest by inhibiting cyclin D1. In addition, vascular endothelial cells also showed a pronounced response to 1D228 due to its expression of TRKB and c-Met. 1D228 suppressed the migration and tube formation of endothelial cells, which are the key functions of tumor angiogenesis. By histology analysis from the in vivo tumor tissues, we confirmed that 1D228 induced cancer cell apoptosis and inhibited tumor angiogenesis, leading to tumor growth retardation. Taken together, compound 1D228 may be a promising candidate for the next generation of c-Met and TRK inhibitors for cancer treatment, and offers a novel potential treatment strategy for gastric and hepatocellular carcinoma.