Molecule Information

General Information of the Molecule (ID: Mol04344)

• Name: Vascular endothelial growth factor receptor 1 (FLT1) ,Homo sapiens
• Synonyms: Fms-like tyrosine kinase 1; Tyrosine-protein kinase FRT; Tyrosine-protein kinase receptor FLT; Vascular permeability factor receptor
• Molecule Type: Protein
• Gene Name: FLT1
• Gene ID: 2321
• Sequence:
  MVSYWDTGVLLCALLSCLLLTGSSSGSKLKDPELSLKGTQHIMQAGQTLHLQCRGEAAHK
  WSLPEMVSKESERLSITKSACGRNGKQFCSTLTLNTAQANHTGFYSCKYLAVPTSKKKE
  T ESAIYIFISDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLI
  PD GKRIIWDSRKGFIISNATYKEIGLLTCEATVNGHLYKTNYLTHRQTNTIIDVQISTP
  RPV KLLRGHTLVLNCTATTPLNTRVQMTWSYPDEKNKRASVRRRIDQSNSHANIFYSVL
  TIDK MQNKDKGLYTCRVRSGPSFKSVNTSVHIYDKAFITVKHRKQQVLETVAGKRSYRL
  SMKVK AFPSPEVVWLKDGLPATEKSARYLTRGYSLIIKDVTEEDAGNYTILLSIKQSNV
  FKNLTA TLIVNVKPQIYEKAVSSFPDPALYPLGSRQILTCTAYGIPQPTIKWFWHPCNH
  NHSEARC DFCSNNEESFILDADSNMGNRIESITQRMAIIEGKNKMASTLVVADSRISGI
  YICIASNK VGTVGRNISFYITDVPNGFHVNLEKMPTEGEDLKLSCTVNKFLYRDVTWIL
  LRTVNNRTM HYSISKQKMAITKEHSITLNLTIMNVSLQDSGTYACRARNVYTGEEILQK
  KEITIRDQEA PYLLRNLSDHTVAISSSTTLDCHANGVPEPQITWFKNNHKIQQEPGIIL
  GPGSSTLFIER VTEEDEGVYHCKATNQKGSVESSAYLTVQGTSDKSNLELITLTCTCVA
  ATLFWLLLTLFI RKMKRSSSEIKTDYLSIIMDPDEVPLDEQCERLPYDASKWEFARERL
  KLGKSLGRGAFGK VVQASAFGIKKSPTCRTVAVKMLKEGATASEYKALMTELKILTHIG
  HHLNVVNLLGACTK QGGPLMVIVEYCKYGNLSNYLKSKRDLFFLNKDAALHMEPKKEKM
  EPGLEQGKKPRLDSV TSSESFASSGFQEDKSLSDVEEEEDSDGFYKEPITMEDLISYSF
  QVARGMEFLSSRKCIH RDLAARNILLSENNVVKICDFGLARDIYKNPDYVRKGDTRLPL
  KWMAPESIFDKIYSTKS DVWSYGVLLWEIFSLGGSPYPGVQMDEDFCSRLREGMRMRAP
  EYSTPEIYQIMLDCWHRD PKERPRFAELVEKLGDLLQANVQQDGKDYIPINAILTGNSG
  FTYSTPAFSEDFFKESISA PKFNSGSSDDVRYVNAFKFMSLERIKTFEELLPNATSMFD
  DYQGDSSTLLASPMLKRFTW TDSKPKASLKIDLRVTSKSKESGLSDVSRPSFCHSSCGH
  VSEGKRRFTYDHAELERKIAC CSPPPDYNSVVLYSTPPI
• Function: Tyrosine-protein kinase that acts as a cell-surface receptorfor VEGFA, VEGFB and PGF, and plays an essential role in thedevelopment of embryonic vasculature, the regulation of angiogenesis,cell survival, cell migration, macrophage function, chemotaxis, andcancer cell invasion. Acts as a positive regulator of postnatal retinalhyaloid vessel regression . May play an essential roleas a negative regulator of embryonic angiogenesis by inhibitingexcessive proliferation of endothelial cells. Can promote endothelialcell proliferation, survival and angiogenesis in adulthood. Itsfunction in promoting cell proliferation seems to be cell-typespecific. Promotes PGF-mediated proliferation of endothelial cells,proliferation of some types of cancer cells, but does not promoteproliferation of normal fibroblasts . Has very high affinityfor VEGFA and relatively low protein kinase activity; may function as anegative regulator of VEGFA signaling by limiting the amount of freeVEGFA and preventing its binding to KDR. Modulates KDR signaling byforming heterodimers with KDR. Ligand binding leads to the activationof several signaling cascades. Activation of PLCG leads to theproduction of the cellular signaling molecules diacylglycerol andinositol 1,4,5-trisphosphate and the activation of protein kinase C.Mediates phosphorylation of PIK3R1, the regulatory subunit ofphosphatidylinositol 3-kinase, leading to activation ofphosphatidylinositol kinase and the downstream signaling pathway.Mediates activation of MAPK1/ERK2, MAPK3/ERK1 and the MAP kinasesignaling pathway, as well as of the AKT1 signaling pathway.Phosphorylates SRC and YES1, and may also phosphorylate CBL. Promotesphosphorylation of AKT1 at 'Ser-473'. Promotes phosphorylation ofPTK2/FAK1 . {ECO:0000250|UniProtKB:P35969,ECO:0000269|PubMed:11141500, ECO:0000269|PubMed:11312102,ECO:0000269|PubMed:11811792, ECO:0000269|PubMed:12796773,ECO:0000269|PubMed:14633857, ECO:0000269|PubMed:15735759,ECO:0000269|PubMed:16685275, ECO:0000269|PubMed:18079407,ECO:0000269|PubMed:18515749, ECO:0000269|PubMed:18583712,ECO:0000269|PubMed:18593464, ECO:0000269|PubMed:20512933,ECO:0000269|PubMed:20551949, ECO:0000269|PubMed:21752276,ECO:0000269|PubMed:7824266, ECO:0000269|PubMed:8248162,ECO:0000269|PubMed:8605350, ECO:0000269|PubMed:9299537,ECO:0000269|Ref.11}.; [Isoform 1]: Phosphorylates PLCG.{ECO:0000269|PubMed:9299537}.; [Isoform 2]: May function as decoy receptor for VEGFA.{ECO:0000269|PubMed:21752276}.; [Isoform 3]: May function as decoy receptor for VEGFA.{ECO:0000269|PubMed:21752276}.; [Isoform 4]: May function as decoy receptor for VEGFA.{ECO:0000269|PubMed:21752276}.; [Isoform 7]: Has a truncated kinase domain; it increasesphosphorylation of SRC at 'Tyr-418' by unknown means and promotes tumorcell invasion. {ECO:0000269|PubMed:20512933}.
• Uniprot ID: VGFR1_HUMAN
• Ensembl ID: ENSG0000010275513
• HGNC ID: HGNC:3763

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 1 drug(s) in total

Sunitinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Clear cell renal cell carcinoma [ICD-11: 2C90.Y] [1]

• Resistant Disease: Clear cell renal cell carcinoma [ICD-11: 2C90.Y]
• Resistant Drug: Sunitinib
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: HIF-1alpha/VEGFA/VEGFR signalling pathway; Regulation; N.A.
• In Vitro Model: 786-O cells; Kidney; Homo sapiens (Human); CVCL_1051
• Experiment for Molecule Alteration: Western blot assay; qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Our study is the first to identify that AUY922 can enhance the sensitivity of ccRCC to sunitinib. AUY922 not only has an inhibitory effect on ccRCC cells, but also enhances the inhibitory effect of sunitinib on ccRCC cells. Additionally, our research is the first to explore the mechanism of AUY922 in ccRCC, demonstrating that it targets the HIF-1/VEGFA/VEGFR pathway by inhibiting HSP90B1.

Clinical Trial Drug(s) 1 drug(s) in total

AUY922

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Clear cell renal cell carcinoma [ICD-11: 2C90.Y] [1]

• Sensitive Disease: Clear cell renal cell carcinoma [ICD-11: 2C90.Y]
• Sensitive Drug: AUY922
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: HIF-1alpha/VEGFA/VEGFR signalling pathway; Regulation; N.A.
• In Vitro Model: ACHN cells; Pleural effusion; Homo sapiens (Human); CVCL_1067
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Our study is the first to identify that AUY922 can enhance the sensitivity of ccRCC to sunitinib. AUY922 not only has an inhibitory effect on ccRCC cells, but also enhances the inhibitory effect of sunitinib on ccRCC cells. Additionally, our research is the first to explore the mechanism of AUY922 in ccRCC, demonstrating that it targets the HIF-1/VEGFA/VEGFR pathway by inhibiting HSP90B1.

References

• Ref 1: AUY922 improves sensitivity to sunitinib in clear cell renal cell carcinoma based on network pharmacology and in vitro experiments. Heliyon. 2024 Jul 18;10(14):e34834.