Despite significant discoveries in basic cancer research and improvements in treatment options and clinical outcomes,cancer remains a major public health concern worldwide.Today,the main focus of cancer research is the...Despite significant discoveries in basic cancer research and improvements in treatment options and clinical outcomes,cancer remains a major public health concern worldwide.Today,the main focus of cancer research is the signaling pathways that are crucial for cell survival,cell proliferation,and cell migration.The aberrant expression of proteins involved in these signaling pathways often leads to abnormal cell growth,cell metastasis,and invasion of healthy tis-sues.One such protein is discoidin domain receptor 1(DDR1)which belongs to the family of receptor tyrosine kinases(RTKs)and is activated upon collagen binding,as a result,downstream signaling pathways are stimulated which are responsible for cell survival,cell growth,adhesion,extracellular matrix remodeling,and cell migration.DDR1 is found to have abnormally elevated expression in various solid tumors,implying a critical role in cancer progression.Tradi-tional cancer treatment involves the use of cytotoxic drugs,chemotherapy,radiotherapy,and surgery,which do not pro-vide long-term survival and often result in cancer recurrence.Numerous small-molecule kinase inhibitors have been synthesized against RTKs including DDR1 and have been highly efficacious in tumor reduction.More recently,targeting the DDR1 extracellular domain(ECD)has garnered much attention from researchers,as inhibiting the DDR1-collagen binding has been attributed to maximizing the likelihood of the combined cytotoxic effect of both immune cells and tar-geted drugs.This review focuses on the structure,function,activation,and signaling partners of DDR1,its role in different solid tumors,andfinally discusses about designing more DDR1 non-kinase inhibitors as promising therapeutic strategies against DDR1-driven tumors.展开更多
The ever-increasing prevalence of noncommunicable diseases(NCDs)represents a major public health burden worldwide.The most common form of NCD is metabolic diseases,which affect people of all ages and usually manifest ...The ever-increasing prevalence of noncommunicable diseases(NCDs)represents a major public health burden worldwide.The most common form of NCD is metabolic diseases,which affect people of all ages and usually manifest their pathobiology through life-threatening cardiovascular complications.A comprehensive understanding of the pathobiology of metabolic diseases will generate novel targets for improved therapies across the common metabolic spectrum.Protein posttranslational modification(PTM)is an important term that refers to biochemical modification of specific amino acid residues in target proteins,which immensely increases the functional diversity of the proteome.The range of PTMs includes phosphorylation,acetylation,methylation,ubiquitination,SUMOylation,neddylation,glycosylation,palmitoylation,myristoylation,prenylation,cholesterylation,glutathionylation,S-nitrosylation,sulfhydration,citrullination,ADPribosylation,and several novel PTMs.Here,we offer a comprehensive review of PTMs and their roles in common metabolic diseases and pathological consequences,including diabetes,obesity,fatty liver diseases,hyperlipidemia,and atherosclerosis.Building upon this framework,we afford a through description of proteins and pathways involved in metabolic diseases by focusing on PTM-based protein modifications,showcase the pharmaceutical intervention of PTMs in preclinical studies and clinical trials,and offer future perspectives.Fundamental research defining the mechanisms whereby PTMs of proteins regulate metabolic diseases will open new avenues for therapeutic intervention.展开更多
In a recent study published in Nature,Wang et al.1 discovered that inhibition of asialoglycoprotein receptor 1(ASGR1)increased cholesterol efflux and thus lowered blood cholesterol and reduced atherosclerosis.This stu...In a recent study published in Nature,Wang et al.1 discovered that inhibition of asialoglycoprotein receptor 1(ASGR1)increased cholesterol efflux and thus lowered blood cholesterol and reduced atherosclerosis.This study offers an emerging new therapeutic target in hypercholesterolemia and its comorbidities and complications(such as fatty liver and atherosclerosis),which are major threats to public health.展开更多
基金T.J.is supported by the Strategic Priority Research Program of the Chinese Academy of Sciences(Grant No.XDB0490000)S.B.and S.M.M.M.are supported by Chinese Academy of Sciences-The Alliance of International Science Organizations for Young Talents+1 种基金W.Z.is supported by the Strategic Priority Research Program of the Chinese Academy of Sciences(Grant No.XDB0490000)P.Z.is supported by the opening project of National&Local Joint Engineering Research Center of Deep Processing Technology for Aquatic Products.
文摘Despite significant discoveries in basic cancer research and improvements in treatment options and clinical outcomes,cancer remains a major public health concern worldwide.Today,the main focus of cancer research is the signaling pathways that are crucial for cell survival,cell proliferation,and cell migration.The aberrant expression of proteins involved in these signaling pathways often leads to abnormal cell growth,cell metastasis,and invasion of healthy tis-sues.One such protein is discoidin domain receptor 1(DDR1)which belongs to the family of receptor tyrosine kinases(RTKs)and is activated upon collagen binding,as a result,downstream signaling pathways are stimulated which are responsible for cell survival,cell growth,adhesion,extracellular matrix remodeling,and cell migration.DDR1 is found to have abnormally elevated expression in various solid tumors,implying a critical role in cancer progression.Tradi-tional cancer treatment involves the use of cytotoxic drugs,chemotherapy,radiotherapy,and surgery,which do not pro-vide long-term survival and often result in cancer recurrence.Numerous small-molecule kinase inhibitors have been synthesized against RTKs including DDR1 and have been highly efficacious in tumor reduction.More recently,targeting the DDR1 extracellular domain(ECD)has garnered much attention from researchers,as inhibiting the DDR1-collagen binding has been attributed to maximizing the likelihood of the combined cytotoxic effect of both immune cells and tar-geted drugs.This review focuses on the structure,function,activation,and signaling partners of DDR1,its role in different solid tumors,andfinally discusses about designing more DDR1 non-kinase inhibitors as promising therapeutic strategies against DDR1-driven tumors.
基金supported by grants from the National Key R&D Program of China(Grant No.2021YFC2500500)the National Natural Science Foundation of China(Grant Nos.82070464,81941022,81530025)+4 种基金the Strategic Priority Research Program of the Chinese Academy of Sciences(Grant No.XDB38010100)supported by Program for Innovative Research Team of The First Affliated Hospital of USTC(CXGG02)Anhui Provincial Key Research and Development Program(Grant No.202104j07020051)Anhui Provincial Natural Science Foundation(Grant No.2208085J08)Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program(Grant No.2017BT01S131)。
文摘The ever-increasing prevalence of noncommunicable diseases(NCDs)represents a major public health burden worldwide.The most common form of NCD is metabolic diseases,which affect people of all ages and usually manifest their pathobiology through life-threatening cardiovascular complications.A comprehensive understanding of the pathobiology of metabolic diseases will generate novel targets for improved therapies across the common metabolic spectrum.Protein posttranslational modification(PTM)is an important term that refers to biochemical modification of specific amino acid residues in target proteins,which immensely increases the functional diversity of the proteome.The range of PTMs includes phosphorylation,acetylation,methylation,ubiquitination,SUMOylation,neddylation,glycosylation,palmitoylation,myristoylation,prenylation,cholesterylation,glutathionylation,S-nitrosylation,sulfhydration,citrullination,ADPribosylation,and several novel PTMs.Here,we offer a comprehensive review of PTMs and their roles in common metabolic diseases and pathological consequences,including diabetes,obesity,fatty liver diseases,hyperlipidemia,and atherosclerosis.Building upon this framework,we afford a through description of proteins and pathways involved in metabolic diseases by focusing on PTM-based protein modifications,showcase the pharmaceutical intervention of PTMs in preclinical studies and clinical trials,and offer future perspectives.Fundamental research defining the mechanisms whereby PTMs of proteins regulate metabolic diseases will open new avenues for therapeutic intervention.
基金supported by the National Natural Science Foundation of China(82100867,81941022,and 81530025)the Anhui Provincial Natural Science Foundation(2108085QH323)+3 种基金the China Postdoctoral Science Foundation(2021M693104)the National Key R&D Program of China(2021YFC2500500)the Strategic Priority Research Program of Chinese Academy of Sciences(XDB38010100)the Program for Innovative Research Team of The First Affiliated Hospital of USTC(CXGG02)。
基金This study was supported by grants from National Key R&D Program of China(No.2021YFC2500500).
文摘In a recent study published in Nature,Wang et al.1 discovered that inhibition of asialoglycoprotein receptor 1(ASGR1)increased cholesterol efflux and thus lowered blood cholesterol and reduced atherosclerosis.This study offers an emerging new therapeutic target in hypercholesterolemia and its comorbidities and complications(such as fatty liver and atherosclerosis),which are major threats to public health.
