FL cytokine receptor; tyrosine-protein kinase receptor FLT3; stem cell tyrosine kinase 1; STK-1; CD135 (FLT3, STK1)

Function

• receptor for the cytokine FLT3LG
• regulates differentiation, proliferation & survival of hematopoietic progenitor cells & of dendritic cells
• promotes phosphorylation of SHC1 & AKT1, & activation of the downstream effector MTOR
• promotes activation of RAS signaling & phosphorylation of downstream kinases, including MAPK1/ERK2 &/or MAPK3/ERK1
• promotes phosphorylation of FES, FER, PTPN6/SHP, PTPN11/SHP-2, PLCG1, & STAT5A &/or STAT5B
  • activation of wild-type FLT3 causes only marginal activation of STAT5A or STAT5B
• mutations that cause constitutive kinase activity promote cell proliferation & resistance to apoptosis via activation of multiple signaling pathways
• present in an inactive conformation in the absence of bound ligand
• FLT3LG binding leads to dimerization & activation by autophosphorylation on several Tyr
  • FLT3LG binding also increases phosphorylation of mutant kinases that are constitutively activated
• dephosphorylated by PTPRJ/DEP-1, PTPN1, PTPN6/SHP-1, & less so by PTPN12
  • dephosphorylation is important for export from the endoplasmic reticulum & location at the cell membrane
• rapidly ubiquitinated by UBE2L6 & the E3 ubiquitin-protein ligase SIAH1 after autophosphorylation, leading to its proteasomal degradation
• interacts with FIZ1 following ligand activation (putative)
• interacts with FES, FER, LYN, FGR, HCK, SRC & GRB2
• interacts with PTPRJ/DEP-1 & PTPN11/SHP2
• interacts with RNF115 & RNF126 (putative)

Structure

• N-glycosylated, contains complex N-glycans with sialic acid
• belongs to the protein kinase superfamily, Tyr protein kinase family, CSF-1/PDGF receptor subfamily
• contains 1 Ig-like C2-type domain (immunoglobulin-like)
• contains 1 protein kinase domain
• juxtamembrane autoregulatory region is important for maintaining the kinase in an inactive state in the absence of bound ligand
  • upon tyrosine phosphorylation, it mediates interaction with the SH2 domains of numerous signaling partners

Compartment

• membrane, single-pass type 1 membrane protein
• endoplasmic reticulum lumen
  • constitutively activated mutant forms with internal tandem duplications are
    • less efficiently transported to the cell surface
    • a significant proportion is retained in an immature form in the endoplasmic reticulum lumen
    • the activated kinase is rapidly targeted for degradation

Alternative splicing

named isoforms=2

Expression

• bone marrow cells
• detected in bone marrow, liver, thymus, spleen & lymph node
• low levels in kidney & pancreas
• highly expressed in T-cell leukemia

Pathology

• somatic mutations leading to constitutive activation of FLT3 are a cause of acute myeloid leukemia (AML)
  • mutations fall into two classes
    • the most common is in-frame internal tandem duplications of variable length in the juxtamembrane region that disrupt the normal regulation of kinase activity
    • point mutations in the kinase domain can result in a constitutively activated kinase

Pharmacology

• quizartinib (Vanflyta) FDA-approved for adult acute myeloid leukemia (AML) with FLT3-ITD (Internal Tandem Duplication)

Laboratory

• FLT3 gene mutation

More general terms

• tyrosine kinase receptor (RTK)
• glycoprotein
• CD antigen

Additional terms

• macrophage colony-stimulating factor 1 receptor; CSF-1 receptor; CSF-1-R; CSF-1R; M-CSF-R; proto-oncogene c-Fms; CD115 (CSF1R, FMS)

Database

• Kegg: http://www.genome.jp/dbget-bin/www_bget?hsa:2322
• OMIM: https://mirror.omim.org/entry/136351
• UniProt: http://www.uniprot.org/uniprot/P36888.html