5x02

Structural highlights

Disease

FLT3_HUMAN Defects in FLT3 are a cause of acute myelogenous leukemia (AML) [MIM:601626. AML is a malignant disease in which hematopoietic precursors are arrested in an early stage of development. Note=Somatic mutations that lead to constitutive activation of FLT3 are frequent in AML patients. These mutations fall into two classes, the most common being in-frame internal tandem duplications of variable length in the juxtamembrane region that disrupt the normal regulation of the kinase activity. Likewise, point mutations in the activation loop of the kinase domain can result in a constitutively activated kinase.^{[1] [2] [3] [4] [5] [6] [7] [8]}

Function

FLT3_HUMAN Tyrosine-protein kinase that acts as cell-surface receptor for the cytokine FLT3LG and regulates differentiation, proliferation and survival of hematopoietic progenitor cells and of dendritic cells. Promotes phosphorylation of SHC1 and AKT1, and activation of the downstream effector MTOR. Promotes activation of RAS signaling and phosphorylation of downstream kinases, including MAPK1/ERK2 and/or MAPK3/ERK1. Promotes phosphorylation of FES, FER, PTPN6/SHP, PTPN11/SHP-2, PLCG1, and STAT5A and/or STAT5B. Activation of wild-type FLT3 causes only marginal activation of STAT5A or STAT5B. Mutations that cause constitutive kinase activity promote cell proliferation and resistance to apoptosis via the activation of multiple signaling pathways.^{[9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19]}

See Also

• Tyrosine kinase 3D structures

References

1. ↑ Mizuki M, Fenski R, Halfter H, Matsumura I, Schmidt R, Muller C, Gruning W, Kratz-Albers K, Serve S, Steur C, Buchner T, Kienast J, Kanakura Y, Berdel WE, Serve H. Flt3 mutations from patients with acute myeloid leukemia induce transformation of 32D cells mediated by the Ras and STAT5 pathways. Blood. 2000 Dec 1;96(12):3907-14. PMID:11090077
2. ↑ Brandts CH, Sargin B, Rode M, Biermann C, Lindtner B, Schwable J, Buerger H, Muller-Tidow C, Choudhary C, McMahon M, Berdel WE, Serve H. Constitutive activation of Akt by Flt3 internal tandem duplications is necessary for increased survival, proliferation, and myeloid transformation. Cancer Res. 2005 Nov 1;65(21):9643-50. PMID:16266983 doi:10.1158/0008-5472.CAN-05-0422
3. ↑ Taketani T, Taki T, Sugita K, Furuichi Y, Ishii E, Hanada R, Tsuchida M, Sugita K, Ida K, Hayashi Y. FLT3 mutations in the activation loop of tyrosine kinase domain are frequently found in infant ALL with MLL rearrangements and pediatric ALL with hyperdiploidy. Blood. 2004 Feb 1;103(3):1085-8. Epub 2003 Sep 22. PMID:14504097 doi:10.1182/blood-2003-02-0418
4. ↑ Kiyoi H, Towatari M, Yokota S, Hamaguchi M, Ohno R, Saito H, Naoe T. Internal tandem duplication of the FLT3 gene is a novel modality of elongation mutation which causes constitutive activation of the product. Leukemia. 1998 Sep;12(9):1333-7. PMID:9737679
5. ↑ Meshinchi S, Stirewalt DL, Alonzo TA, Boggon TJ, Gerbing RB, Rocnik JL, Lange BJ, Gilliland DG, Radich JP. Structural and numerical variation of FLT3/ITD in pediatric AML. Blood. 2008 May 15;111(10):4930-3. doi: 10.1182/blood-2008-01-117770. Epub 2008, Feb 27. PMID:18305215 doi:10.1182/blood-2008-01-117770
6. ↑ 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. Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood. 2001 Apr 15;97(8):2434-9. PMID:11290608
7. ↑ Nakao M, Yokota S, Iwai T, Kaneko H, Horiike S, Kashima K, Sonoda Y, Fujimoto T, Misawa S. Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. Leukemia. 1996 Dec;10(12):1911-8. PMID:8946930
8. ↑ Abu-Duhier FM, Goodeve AC, Wilson GA, Care RS, Peake IR, Reilly JT. Identification of novel FLT-3 Asp835 mutations in adult acute myeloid leukaemia. Br J Haematol. 2001 Jun;113(4):983-8. PMID:11442493
9. ↑ Small D, Levenstein M, Kim E, Carow C, Amin S, Rockwell P, Witte L, Burrow C, Ratajczak MZ, Gewirtz AM, et al.. STK-1, the human homolog of Flk-2/Flt-3, is selectively expressed in CD34+ human bone marrow cells and is involved in the proliferation of early progenitor/stem cells. Proc Natl Acad Sci U S A. 1994 Jan 18;91(2):459-63. PMID:7507245
10. ↑ Zhang S, Mantel C, Broxmeyer HE. Flt3 signaling involves tyrosyl-phosphorylation of SHP-2 and SHIP and their association with Grb2 and Shc in Baf3/Flt3 cells. J Leukoc Biol. 1999 Mar;65(3):372-80. PMID:10080542
11. ↑ Mizuki M, Fenski R, Halfter H, Matsumura I, Schmidt R, Muller C, Gruning W, Kratz-Albers K, Serve S, Steur C, Buchner T, Kienast J, Kanakura Y, Berdel WE, Serve H. Flt3 mutations from patients with acute myeloid leukemia induce transformation of 32D cells mediated by the Ras and STAT5 pathways. Blood. 2000 Dec 1;96(12):3907-14. PMID:11090077
12. ↑ Brandts CH, Sargin B, Rode M, Biermann C, Lindtner B, Schwable J, Buerger H, Muller-Tidow C, Choudhary C, McMahon M, Berdel WE, Serve H. Constitutive activation of Akt by Flt3 internal tandem duplications is necessary for increased survival, proliferation, and myeloid transformation. Cancer Res. 2005 Nov 1;65(21):9643-50. PMID:16266983 doi:10.1158/0008-5472.CAN-05-0422
13. ↑ Rocnik JL, Okabe R, Yu JC, Lee BH, Giese N, Schenkein DP, Gilliland DG. Roles of tyrosine 589 and 591 in STAT5 activation and transformation mediated by FLT3-ITD. Blood. 2006 Aug 15;108(4):1339-45. Epub 2006 Apr 20. PMID:16627759 doi:10.1182/blood-2005-11-011429
14. ↑ Kikushige Y, Yoshimoto G, Miyamoto T, Iino T, Mori Y, Iwasaki H, Niiro H, Takenaka K, Nagafuji K, Harada M, Ishikawa F, Akashi K. Human Flt3 is expressed at the hematopoietic stem cell and the granulocyte/macrophage progenitor stages to maintain cell survival. J Immunol. 2008 Jun 1;180(11):7358-67. PMID:18490735
15. ↑ Voisset E, Lopez S, Chaix A, Georges C, Hanssens K, Prebet T, Dubreuil P, De Sepulveda P. FES kinases are required for oncogenic FLT3 signaling. Leukemia. 2010 Apr;24(4):721-8. doi: 10.1038/leu.2009.301. Epub 2010 Jan 28. PMID:20111072 doi:10.1038/leu.2009.301
16. ↑ Chen W, Drakos E, Grammatikakis I, Schlette EJ, Li J, Leventaki V, Staikou-Drakopoulou E, Patsouris E, Panayiotidis P, Medeiros LJ, Rassidakis GZ. mTOR signaling is activated by FLT3 kinase and promotes survival of FLT3-mutated acute myeloid leukemia cells. Mol Cancer. 2010 Nov 10;9:292. doi: 10.1186/1476-4598-9-292. PMID:21067588 doi:10.1186/1476-4598-9-292
17. ↑ Arora D, Stopp S, Bohmer SA, Schons J, Godfrey R, Masson K, Razumovskaya E, Ronnstrand L, Tanzer S, Bauer R, Bohmer FD, Muller JP. Protein-tyrosine phosphatase DEP-1 controls receptor tyrosine kinase FLT3 signaling. J Biol Chem. 2011 Apr 1;286(13):10918-29. doi: 10.1074/jbc.M110.205021. Epub 2011, Jan 24. PMID:21262971 doi:10.1074/jbc.M110.205021
18. ↑ Zheng R, Bailey E, Nguyen B, Yang X, Piloto O, Levis M, Small D. Further activation of FLT3 mutants by FLT3 ligand. Oncogene. 2011 Sep 22;30(38):4004-14. doi: 10.1038/onc.2011.110. Epub 2011 Apr, 25. PMID:21516120 doi:10.1038/onc.2011.110
19. ↑ Taketani T, Taki T, Sugita K, Furuichi Y, Ishii E, Hanada R, Tsuchida M, Sugita K, Ida K, Hayashi Y. FLT3 mutations in the activation loop of tyrosine kinase domain are frequently found in infant ALL with MLL rearrangements and pediatric ALL with hyperdiploidy. Blood. 2004 Feb 1;103(3):1085-8. Epub 2003 Sep 22. PMID:14504097 doi:10.1182/blood-2003-02-0418
20. ↑ Yamaura T, Nakatani T, Uda K, Ogura H, Shin W, Kurokawa N, Saito K, Fujikawa N, Date T, Takasaki M, Terada D, Hirai A, Akashi A, Chen F, Adachi Y, Ishikawa Y, Hayakawa F, Hagiwara S, Naoe T, Kiyoi H. A novel irreversible FLT3 inhibitor, FF-10101, shows excellent efficacy against AML cells with FLT3 mutations. Blood. 2018 Jan 25;131(4):426-438. doi: 10.1182/blood-2017-05-786657. Epub 2017, Nov 29. PMID:29187377 doi:http://dx.doi.org/10.1182/blood-2017-05-786657