Contents

Search

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 Laboratory: - FLT3 gene mutation Pharmacology: - quizartinib (Vanflyta) FDA-approved for adult acute myeloid leukemia (AML) with FLT3-ITD (Internal Tandem Duplication) [3]

Related

CD135 blasts in blood CD135 blasts in bone marrow macrophage colony-stimulating factor 1 receptor; CSF-1 receptor; CSF-1-R; CSF-1R; M-CSF-R; proto-oncogene c-Fms; CD115 (CSF1R, FMS)

General

cluster-of-differentiation antigen; cluster designation antigen; CD antigen glycoprotein tyrosine kinase receptor (RTK)

Properties

SIZE: entity length = 993 aa MW = 113 kD COMPARTMENT: cellular membrane STATE: active state MOTIF: signal sequence {1-26} N-glycosylation site {N43} N-glycosylation site {N100} N-glycosylation site {N151} immunoglobulin superfamily domain {253-343} MOTIF: N-glycosylation site {N306} N-glycosylation site {N323} N-glycosylation site {N351} N-glycosylation site {N354} N-glycosylation site {N473} N-glycosylation site {N502} N-glycosylation site {N541} transmembrane domain {544-563} kinase domain SITE: 610-943 MOTIF: ATP-binding site NAME: ATP-binding site SITE: 616-624 ATP-binding site NAME: ATP-binding site SITE: 644-644 aspartate residue {D811}

Database Correlations

OMIM 136351 MORBIDMAP 136351 UniProt P36888 PFAM correlations Kegg hsa:2322 ENZYME 2.7.10.1

References

  1. UniProt :accession P36888
  2. Atlas of genetics & cytogenetics in oncology & haematology http://atlasgeneticsoncology.org/genes/FLT3ID144.html
  3. Otto MA FDA Approves Quizartinib for Newly Diagnosed AML. Medscape. July 20, 2023 https://www.medscape.com/viewarticle/994618