Although VEGF-B was discovered as a VEGF-A homolog a long time ago,the angiogenic effect of VEGF-B remains poorly understood with limited and diverse findings from different groups.Notwithstanding,drugs that inhibit V...Although VEGF-B was discovered as a VEGF-A homolog a long time ago,the angiogenic effect of VEGF-B remains poorly understood with limited and diverse findings from different groups.Notwithstanding,drugs that inhibit VEGF-B together with other VEGF family members are being used to treat patients with various neovascular diseases.It is therefore critical to have a better understanding of the angiogenic effect of VEGF-B and the underlying mechanisms.Using comprehensive in vitro and in vivo methods and models,we reveal here for the first time an unexpected and surprising function of VEGF-B as an endogenous inhibitor of angiogenesis by inhibiting the FGF2/FGFR1 pathway when the latter is abundantly expressed.Mechanistically,we unveil that VEGF-B binds to FGFR1,induces FGFR1/VEGFR1 complex formation,and suppresses FGF2-induced Erk activation,and inhibits FGF2-driven angiogenesis and tumor growth.Our work uncovers a previously unrecognized novel function of VEGF-B in tethering the FGF2/FGFR1 pathway.Given the anti-angiogenic nature of VEGF-B under conditions of high FGF2/FGFR1 levels,caution is warranted when modulating VEGF-B activity to treat neovascular diseases.展开更多
Unconventional protein export/secretion(UPE/UPS),in contrast to the classical ER-Golgi-dependent export/secretion of proteins with a leader sequence(signal peptide),employs multiple means to release leaderless cargoes...Unconventional protein export/secretion(UPE/UPS),in contrast to the classical ER-Golgi-dependent export/secretion of proteins with a leader sequence(signal peptide),employs multiple means to release leaderless cargoes(and in some special cases,cargoes with a leader sequence)to the extracellular space.By far,two major types of UPE have been classified,vesicle-independent UPE and vesicle-dependent UPE.In the former,UPE cargoes can directly translocate across the plasma membrane from the cytoplasm without the assistance of a vesicle carrier.In the latter,UPE cargoes translocate into the lumen of a vesicle which then delivers them out of the cell through membrane trafficking.Both types of UPE require multiple unconventional solutions to complete secretion.Here,we briefly discuss the multiple strategies for a UPE cargo release,focusing on two key steps of leaderless cargoes release in UPE:protein translocation and membrane trafficking.展开更多
基金This study is supported by the State Key Laboratory of Ophthalmology,Zhongshan Ophthalmic Center,Sun Yat-sen University,and Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science,Guangzhou 510060,P.R.Chinathe National Natural Science Foundation of China(82150710555 and 82220108016 to X.Li,81970823 to Jin Yao and 81830013 to J.O.)+4 种基金a Key Research and Development Plan of Shandong Province(2016GSF201100)the Fundamental Research Funds for the Central Universities(19ykpy151)the long-term structural Methusalem funding by the Flemish Government,Belgiumthe Deutsche Forschungsge-meinschaft(Project No.:394046768-SFB1366)the DZHK partner site Mannheim/Heidelberg to H.F.L.,an ERA PerMed 2020 JTC grant“PROGRESS”.
文摘Although VEGF-B was discovered as a VEGF-A homolog a long time ago,the angiogenic effect of VEGF-B remains poorly understood with limited and diverse findings from different groups.Notwithstanding,drugs that inhibit VEGF-B together with other VEGF family members are being used to treat patients with various neovascular diseases.It is therefore critical to have a better understanding of the angiogenic effect of VEGF-B and the underlying mechanisms.Using comprehensive in vitro and in vivo methods and models,we reveal here for the first time an unexpected and surprising function of VEGF-B as an endogenous inhibitor of angiogenesis by inhibiting the FGF2/FGFR1 pathway when the latter is abundantly expressed.Mechanistically,we unveil that VEGF-B binds to FGFR1,induces FGFR1/VEGFR1 complex formation,and suppresses FGF2-induced Erk activation,and inhibits FGF2-driven angiogenesis and tumor growth.Our work uncovers a previously unrecognized novel function of VEGF-B in tethering the FGF2/FGFR1 pathway.Given the anti-angiogenic nature of VEGF-B under conditions of high FGF2/FGFR1 levels,caution is warranted when modulating VEGF-B activity to treat neovascular diseases.
基金supported by the National Natural Science Foundation of China(32130023,91854114,and 32061143009)the Ministry of Science and Technology of the People’s Republic of China(2019YFA0508602 and 2021YFA0804802)the Beijing Natural Science Foundation(JQ20028)。
文摘Unconventional protein export/secretion(UPE/UPS),in contrast to the classical ER-Golgi-dependent export/secretion of proteins with a leader sequence(signal peptide),employs multiple means to release leaderless cargoes(and in some special cases,cargoes with a leader sequence)to the extracellular space.By far,two major types of UPE have been classified,vesicle-independent UPE and vesicle-dependent UPE.In the former,UPE cargoes can directly translocate across the plasma membrane from the cytoplasm without the assistance of a vesicle carrier.In the latter,UPE cargoes translocate into the lumen of a vesicle which then delivers them out of the cell through membrane trafficking.Both types of UPE require multiple unconventional solutions to complete secretion.Here,we briefly discuss the multiple strategies for a UPE cargo release,focusing on two key steps of leaderless cargoes release in UPE:protein translocation and membrane trafficking.
