CD135

FLT3
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1RJB, 3QS7, 3QS9, 4RT7, 4XUF
Identifiers
Aliases	FLT3, CD135, FLK-2, FLK2, STK1, fms related tyrosine kinase 3, fms related receptor tyrosine kinase 3
External IDs	OMIM: 136351 MGI: 95559 HomoloGene: 3040 GeneCards: FLT3
Gene location (Human) Chr. Chromosome 13 (human)[1] Band 13q12.2 Start 28,003,274 bp[1] End 28,100,592 bp[1]
Gene location (Mouse) Chr. Chromosome 5 (mouse)[2] Band 5 86.88 cM|5 G3 Start 147,267,551 bp[2] End 147,337,299 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in cerebellar hemisphere monocyte bone marrow cells lymph node body of pancreas spleen appendix gallbladder right lung blood Top expressed in superior olivary complex facial motor nucleus red nucleus cochlear nuclei motor neuron Region IV of hippocampus proper Purkinje cell anterior horn of spinal cord nerve inferior colliculus More reference expression data BioGPS More reference expression data
Gene ontology Molecular function vascular endothelial growth factor-activated receptor activity nucleotide binding protein kinase activity transferase activity protein homodimerization activity kinase activity protein binding cytokine receptor activity transmembrane receptor protein tyrosine kinase activity protein tyrosine kinase activity ATP binding protein self-association protein-containing complex binding glucocorticoid receptor binding 1-phosphatidylinositol-3-kinase activity receptor tyrosine kinase transmembrane signaling receptor activity Cellular component cytoplasm integral component of membrane cytosol endoplasmic reticulum lumen membrane integral component of plasma membrane nucleus plasma membrane endoplasmic reticulum protein-containing complex receptor complex Biological process leukocyte homeostasis regulation of apoptotic process dendritic cell differentiation cell differentiation myeloid progenitor cell differentiation positive regulation of MAP kinase activity phosphorylation transmembrane receptor protein tyrosine kinase signaling pathway common myeloid progenitor cell proliferation positive regulation of tyrosine phosphorylation of STAT protein cellular response to cytokine stimulus positive regulation of phosphatidylinositol 3-kinase activity protein phosphorylation pro-B cell differentiation cellular response to glucocorticoid stimulus animal organ regeneration response to organonitrogen compound positive regulation of cell population proliferation lymphocyte proliferation protein autophosphorylation positive regulation of phosphatidylinositol 3-kinase signaling peptidyl-tyrosine phosphorylation B cell differentiation positive regulation of MAPK cascade vascular endothelial growth factor signaling pathway cytokine-mediated signaling pathway hemopoiesis MAPK cascade phosphatidylinositol-3-phosphate biosynthetic process negative regulation of signal transduction viral process negative regulation of apoptotic process positive regulation of ERK1 and ERK2 cascade hematopoietic progenitor cell differentiation leukocyte differentiation lymphocyte differentiation Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 2322 14255 Ensembl ENSG00000122025 ENSMUSG00000042817 UniProt P36888 Q00342 RefSeq (mRNA) NM_004119 NM_010229 RefSeq (protein) NP_004110 NP_034359 Location (UCSC) Chr 13: 28 – 28.1 Mb Chr 5: 147.27 – 147.34 Mb PubMed search [3] [4]
Wikidata
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Cluster of differentiation antigen 135 (CD135) also known as fms like tyrosine kinase 3 (FLT-3 with fms standing for "feline McDonough sarcoma"), receptor-type tyrosine-protein kinase FLT3, or fetal liver kinase-2 (Flk2) is a protein that in humans is encoded by the FLT3 gene. FLT3 is a cytokine receptor which belongs to the receptor tyrosine kinase class III. CD135 is the receptor for the cytokine Flt3 ligand (FLT3L).

It is expressed on the surface of many hematopoietic progenitor cells. Signalling of FLT3 is important for the normal development of haematopoietic stem cells and progenitor cells.

The FLT3 gene is one of the most frequently mutated genes in acute myeloid leukemia (AML).^[5] High levels of wild-type FLT3 have been reported for blast cells of some AML patients without FLT3 mutations. These high levels may be associated with worse prognosis.

Structure

FLT3 is composed of five extracellular immunoglobulin-like domains, an extracellular domain, a transmembrane domain, a juxtamembrane domain and a tyrosine-kinase domain consisting of 2 lobes that are connected by a tyrosine-kinase insert. Cytoplasmic FLT3 undergoes glycosylation, which promotes localization of the receptor to the membrane.^[6]

Function

CD135 is a class III receptor tyrosine kinase. When this receptor binds to FLT3L a ternary complex is formed in which two FLT3 molecules are bridged by one (homodimeric) FLT3L.^[7] The formation of such complex brings the two intracellular domains in close proximity to each other, eliciting initial trans-phosphorylation of each kinase domain. This initial phosphorylation event further activates the intrinsic tyrosine kinase activity, which in turn phosphorylates and activates signal transduction molecules that propagate the signal in the cell. Signaling through CD135 plays a role in cell survival, proliferation, and differentiation. CD135 is important for lymphocyte (B cell and T cell) development.

Two cytokines that down modulate FLT3 activity (& block FLT3-induced hematopoietic activity) are:

• TNF-alpha (Tumor necrosis factor-alpha)
• TGF-beta (Transforming growth factor-beta)

TGF-beta especially, decreases FLT3 protein levels and reverses the FLT3L-induced decrease in the time that hematopoietic progenitors spend in the G1-phase of the cell cycle.^[6]

Clinical significance

Cell surface marker

Cluster of differentiation (CD) molecules are markers on the cell surface, as recognized by specific sets of antibodies, used to identify the cell type, stage of differentiation and activity of a cell. In mice, CD135 is expressed on several hematopoietic (blood) cells, including long- and short-term reconstituting hematopoietic stem cells (HSC) and other progenitors like multipotent progenitors (MPPs) and common lymphoid progenitors (CLP).^[8]

Role in cancer

CD135 is a proto-oncogene, meaning that mutations of this protein can lead to cancer.^[9] Mutations of the FLT3 receptor can lead to the development of leukemia, a cancer of bone marrow hematopoietic progenitors. Internal tandem duplications of FLT3 (FLT3-ITD) are the most common mutations associated with acute myelogenous leukemia (AML) and are a prognostic indicator associated with adverse disease outcome.

FLT3 inhibitors

Gilteritinib, a dual FLT3-AXL tyrosine kinase inhibitor^[10] has completed a phase 3 trial of relapsed/refractory acute myeloid leukemia in patients with FLT3 ITD or TKD mutations.^[11] In 2017, gilteritinib gained FDA orphan drug status for AML.^[12] In November 2018, the FDA approved gilteritinib (Xospata) for treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with a FLT3 mutation as detected by an FDA-approved test.^[13]

In July 2023, quizartinib (Vanflyta) was also approved for the treatment of newly diagnosed AML with FLT3 internal tandem duplication (ITD)-positive, as detected by an FDA-approved test.^[14] Precisely, it should be used with standard cytarabine and anthracycline induction and cytarabine consolidation, and as maintenance monotherapy following consolidation chemotherapy.^[14]

Midostaurin was approved by the FDA in April 2017 for the treatment of adult patients with newly diagnosed AML who are positive for oncogenic FLT3, in combination with chemotherapy.^[15] The drug is approved for use with a companion diagnostic, the LeukoStrat CDx FLT3 Mutation Assay, which is used to detect the FLT3 mutation in patients with AML.

Sorafenib has been reported to show significant activity against Flt3-ITD positive acute myelogenous leukemia.^[16][17]

Sunitinib also inhibits Flt3.

Lestaurtinib is in clinical trials.

A paper published in Nature in April 2012 studied patients who developed resistance to FLT3 inhibitors, finding specific DNA sites contributing to that resistance and highlighting opportunities for future development of inhibitors that could take into account the resistance-conferring mutations for a more potent treatment.^[18]

See also

References

Further reading

External links

• CD135+Antigen at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Human FLT3 genome location and FLT3 gene details page in the UCSC Genome Browser.
• Overview of all the structural information available in the PDB for UniProt: P36888 (Receptor-type tyrosine-protein kinase FLT3) at the PDBe-KB.