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Cd135

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Title: Cd135  
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Subject: DDR1, Fibroblast growth factor receptor 4, TEK tyrosine kinase, Kinase insert domain receptor, Discoidin domain-containing receptor 2
Collection: Ec 2.7.10, Tyrosine Kinases
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Cd135

Fms-related tyrosine kinase 3
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols  ; CD135; FLK-2; FLK2; STK1
External IDs ChEMBL: GeneCards:
EC number
RNA expression pattern
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)
RefSeq (protein)
Location (UCSC)
PubMed search

Cluster of differentiation antigen 135 (CD135) also known as Fms-like tyrosine kinase 3 (FLT-3), 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).[1] Besides, 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.

Contents

  • Structure 1
  • Function 2
  • Clinical significance 3
    • Cell surface marker 3.1
    • Role in cancer 3.2
    • FLT3 inhibitors 3.3
  • See also 4
  • References 5
  • Further reading 6
  • External links 7

Structure

FLT3 is composed of five extracellular immunoglobulin-like domains, 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.[2]

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.[3] 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, but not for the development of other blood cells (myeloid development).

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

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.[2]

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. CD135 is an important cell surface marker used to identify certain types of hematopoietic (blood) progenitors in the bone marrow. Specifically, multipotent progenitors (MPP) and common lymphoid progenitors (CLP) express high surface levels of CD135. This marker is therefore used to differentiate hematopoietic stem cells (HSC), which are CD135 negative, from MPPs, which are CD135 positive. (See Lymphopoiesis#Labeling lymphopoiesis)

Role in cancer

CD135 is a proto-oncogene, meaning that mutations of this protein can lead to cancer.[4] 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

Quizartinib (AC220) and midostaurin were in phase II clinical trials for AML patients with FLT3 mutations.[5][6] Quizartinib had good results in a phase II clinical trial for refractory AML - particularly in patients who went on to have a stem cell transplant.[7]

Sorafenib has been reported to show significant activity against Flt3-ITD positive acute myelogenous leukemia.[8][9]

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.[10]

See also

References

  1. ^ Yamamoto Y, Kiyoi H, Nakano Y, Suzuki R, Kodera Y, Miyawaki S, Asou N, Kuriyama K, Yagasaki F, Shimazaki C, Akiyama H, Saito K, Nishimura M, Motoji T, Shinagawa K, Takeshita A, Saito H, Ueda R, Ohno R, Naoe T (April 2001). "Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies". Blood 97 (8): 2434–9.  
  2. ^ a b "FLT3 Signaling". Pathway Central. SABiosciences. 
  3. ^ Verstraete K, Vandriessche G, Januar M, Elegheert J, Shkumatov AV, Desfosses A, Van Craenenbroeck K, Svergun DI, Gutsche I, Vergauwen B, Savvides SN (February 2011). "Structural insights into the extracellular assembly of the hematopoietic Flt3 signaling complex". Blood 118 (1): 60–68.  
  4. ^ Huret J-L. "FLT3 (FMS-like tyrosine kinase 3)". Atlas of Genetics and Cytogenetics in Oncology and Haematology. University Hospital of Poitiers. 
  5. ^ "Efficacy Study for AC220 to Treat Acute Myeloid Leukemia (AML)". ClinicalTrials.gov. U.S. National Institutes of Health. 
  6. ^ "Astellas Pays $40M Up Front to Develop Ambit’s FLT3 Kinase Inhibitors". Highlights. Genetic Engineering & Biotechnology News. 2009-12-18. 
  7. ^ Gever J (2012-12-09). "Drug Tames Refractory AML". ASH: Hematology Latest News. MedPage Today, LLC. 
  8. ^ Metzelder S, Wang Y, Wollmer E, Wanzel M, Teichler S, Chaturvedi A, Eilers M, Enghofer E, Neubauer A, Burchert A (June 2009). "Compassionate use of sorafenib in FLT3-ITD-positive acute myeloid leukemia: sustained regression before and after allogeneic stem cell transplantation". Blood 113 (26): 6567–71.  
  9. ^ Zhang W, Konopleva M, Shi YX, McQueen T, Harris D, Ling X, Estrov Z, Quintás-Cardama A, Small D, Cortes J, Andreeff M (February 2008). "Mutant FLT3: a direct target of sorafenib in acute myelogenous leukemia". J. Natl. Cancer Inst. 100 (3): 184–98.  
  10. ^ http://www.nature.com/nature/journal/v485/n7397/full/nature11016.html

Further reading

  • Masson K, Rönnstrand L (2009). "Oncogenic signaling from the hematopoietic growth factor receptors c-Kit and Flt3.". Cell.Signal. 21 (12): 1717–1726.  
  • Reilly JT (2003). "FLT3 and its role in the pathogenesis of acute myeloid leukaemia.". Leuk. Lymphoma 44 (1): 1–7.  
  • Kottaridis PD, Gale RE, Linch DC (2003). "Prognostic implications of the presence of FLT3 mutations in patients with acute myeloid leukemia.". Leuk. Lymphoma 44 (6): 905–13.  
  • Gilliland DG (2004). "FLT3-activating mutations in acute promyelocytic leukaemia: a rationale for risk-adapted therapy with FLT3 inhibitors.". Best practice & research. Clinical haematology 16 (3): 409–17.  
  • Drexler HG, Quentmeier H (2005). "FLT3: receptor and ligand.". Growth Factors 22 (2): 71–3.  
  • Naoe T, Kiyoi H (2005). "Normal and oncogenic FLT3.". Cell. Mol. Life Sci. 61 (23): 2932–8.  
  • Sternberg DW, Licht JD (2005). "Therapeutic intervention in leukemias that express the activated fms-like tyrosine kinase 3 (FLT3): opportunities and challenges.". Curr. Opin. Hematol. 12 (1): 7–13.  
  • Marcucci G, Mrózek K, Bloomfield CD (2005). "Molecular heterogeneity and prognostic biomarkers in adults with acute myeloid leukemia and normal cytogenetics.". Curr. Opin. Hematol. 12 (1): 68–75.  
  • Markovic A, MacKenzie KL, Lock RB (2005). "FLT-3: a new focus in the understanding of acute leukemia.". Int. J. Biochem. Cell Biol. 37 (6): 1168–72.  
  • Zheng R, Small D (2006). "Mutant FLT3 signaling contributes to a block in myeloid differentiation.". Leuk. Lymphoma 46 (12): 1679–87.  
  • Parcells BW, Ikeda AK, Simms-Waldrip T, et al. (2007). "FMS-like tyrosine kinase 3 in normal hematopoiesis and acute myeloid leukemia.". Stem Cells 24 (5): 1174–84.  
  • Stubbs MC, Armstrong SA (2007). "FLT3 as a therapeutic target in childhood acute leukemia.". Current drug targets 8 (6): 703–14.  

External links

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