Pathway maps

Development_Flt3 signaling
Development_Flt3 signaling

Object List (links open in MetaCore):

Fyn, PDK (PDPK1), GAB2, PI3K reg class IA (p85), CRK, MEKK1(MAP3K1), GAB1, p38 MAPK, SHP-2, MEK3(MAP2K3), MEK4(MAP2K4), c-Cbl, GRB2, c-Src, CDC42, CrkL, PAK1, PI3K cat class IA, SOS, FLT3, H-Ras, MKK7 (MAP2K7), p90Rsk, PtdIns(4,5)P2, AKT(PKB), PtdIns(3,4,5)P3, MEK2(MAP2K2), MEK6(MAP2K6), MEKK4(MAP3K4), VAV-1, Bcl-XL, JNK1(MAPK8), BAD, STAT5A, MEK1(MAP2K1), ATF-2, 2.7.1.153, SHIP, c-Raf-1, FLT3 ligand, Erk (MAPK1/3), Rac1, c-Jun, Shc

Description

Flt3 signaling

FMS-like tyrosine kinase 3 ( FLT3 ) belongs to the subclass III family of receptor tyrosine kinases and it is expressed mainly in early myeloid and lymphoid progenitor cells. Its activation leads mainly to proliferation and survival [1], [2]. FLT3 consists of five immunoglobulin-like extracellular domains, a transmembrane domain, a juxtamembrane domain and two intracellular tyrosine kinase domains linked by a kinase-insert domain [1].

FLT3 ligand binds the monomeric form of FLT3 receptor and induces receptor dimerization. This promotes autophosphorylation of the tyrosine-kinase domains FLT3, thereby activating the FLT3 and downstream effectors [1], [3].

The exact mechanism of action FLT3 remains unknown. It was is proposed that activated FLT3 stimulates some members of Src family of protein tyrosine kinases (e.g., c-src sarcoma viral oncogene homolog ( c-Src ) or Fyn ) [4], [3]. Then these tyrosine kinases (or some other tyrosine kinases) may phosphorylate several adaptor proteins. For example, there are Src homology 2 domain containing transforming protein 1 ( Shc ) [5], [6], Cas-Br-M ecotropic retroviral transforming sequence ( c-Cbl ) [5], GRB2-associated binding proteins 1 and 2 ( Gab1 and Gab2 ) [7].

These proteins along with Growth factor receptor-bound protein ( GRB2 ), Protein tyrosine phosphatase, non-receptor type 11 ( SHP-2 ), Inositol polyphosphate-5-phosphatase, 145kDa ( SHIP ) [8], [7], [9], v-crk sarcoma virus CT10 oncogene homolog ( CRK ) and/or v-crk sarcoma virus CT10 oncogene homolog-like ( CrkL ) [10] participate in transition of FLT3 signaling.

It is known, that FLT3 may activate v-akt murine thymoma viral oncogene homolog ( AKT ) [11], [9], Mitogen-activated protein kinase ERK [8], [12], [9], Mitogen-activated protein kinase 8 ( JNK1 ) and Mitogen-activated protein kinase p38 [10].

It is proposed, that complex adaptors composed of Shc, c-Cbl, Gab1, Gab2, GRB2, SHP-2, SHIP and CrkL participates in Phosphoinositide-3-kinase ( PI3K ) activation [8], [7], [9], [10]. Activated PI3K stimulates the conversion of Phosphatidylinositol-4,5-bisphosphate ( PI(4,5)P2 ) into Phosphatidylinositol-3,4,5-trisphosphate ( PI(3,4,5)P3 ). PI(3,4,5)P3 binds to the pleckstrin-homology domain of AKT, recruits AKT to the plasma membrane, and exposes AKT to Phosphorylation at by 3-phosphoinositide-dependent protein kinase 1 ( PDK ) [13].

AKT may suppress apoptosis, for instance, by inhibiting BCL2-antagonist of cell death ( BAD ) [11], [9].

In addition, it is possible that PI3K may stimulate Guanine nucleotide exchange factor VAV-1, thus participating in JNK and p38 activation, [14], [10].

It is known, that VAV-1 may activate members RAS superfamily of small GTP-binding proteins, e.g. Ras-related C3 botulinum toxin substrate 1 ( Rac1 ) and Cell division cycle 42 ( CDC42 ) [15]. Then, activated Rac1 and CDC42 may stimulate p21-activated kinase 1 ( PAK1 )/ Mitogen-activated protein kinase kinase kinase 1 ( MEKK1 )/ Dual specificity mitogen-activated protein kinase kinase 4 ( MEK4 ) and/or 7 ( MEK7 )/ JNK1 cascade [16]. FLT3 -activated JNK1 have anti-apoptotic function (it is possibly, via inhibition BAD [17] ). In addition, JNK1 phosphorylates transcription factor Jun oncogene ( c-Jun ), which participates in anti-apoptosis (probably,, via activation of transcription BCL2-like 1 ( Bcl-XL ) [18] ) and proliferation [10].

Moreover, Rac1 and CDC42 may stimulate Mitogen-activated protein kinase kinase kinase 4 ( MEKK4 )/ Dual specificity mitogen-activated protein kinase kinase 3 ( MEK3 ) and/or 6 ( MEK6 )/ p38 cascade [16]. p38 phosphorylates Activated transcription factor 2 ( ATF-2 ), in turn, may participate in anti-apoptosis [10].

On the other hand, FLT3 -activated adaptors Shc and GRB2 participate in ERK activation via Son of sevenless ( SOS )/ Harvey rat sarcoma virus oncogene ( H-Ras )/ v-raf-1 murine leukemia viral oncogene homolog 1 ( c-Raf-1 )/ MAPK kinase 1 ( MEK1 ) and 2 ( MEK2 )/ Erk cascade. Erk cascade stimulates proliferation of hematopoietic cells, e.g. via phosphorylation Signal transducer and activator of transcription 5A ( STAT5A ) [12] or via other pathways [8], [6], [3]. In addition, FLT3/ ERK pathway participates inhibition BAD by phosphorylation [11], possibly, via Ribosomal protein S6 kinases ( p90RSK ) [19].

References:

  1. Stirewalt DL, Radich JP
    The role of FLT3 in haematopoietic malignancies. Nature reviews. Cancer 2003 Sep;3(9):650-65
  2. Drexler HG, Quentmeier H
    FLT3: receptor and ligand. Growth factors (Chur, Switzerland) 2004 Jun;22(2):71-3
  3. Heiss E, Masson K, Sundberg C, Pedersen M, Sun J, Bengtsson S, Ronnstrand L
    Identification of Y589 and Y599 in the juxtamembrane domain of Flt3 as ligand-induced autophosphorylation sites involved in binding of Src family kinases and the protein tyrosine phosphatase SHP2. Blood 2006 Sep 1;108(5):1542-50
  4. Dosil M, Wang S, Lemischka IR
    Mitogenic signalling and substrate specificity of the Flk2/Flt3 receptor tyrosine kinase in fibroblasts and interleukin 3-dependent hematopoietic cells. Molecular and cellular biology 1993 Oct;13(10):6572-85
  5. Lavagna-Sevenier C, Marchetto S, Birnbaum D, Rosnet O
    FLT3 signaling in hematopoietic cells involves CBL, SHC and an unknown P115 as prominent tyrosine-phosphorylated substrates. Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 1998 Mar;12(3):301-10
  6. Marchetto S, Fournier E, Beslu N, Aurran-Schleinitz T, Dubreuil P, Borg JP, Birnbaum D, Rosnet O
    SHC and SHIP phosphorylation and interaction in response to activation of the FLT3 receptor. Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 1999 Sep;13(9):1374-82
  7. Zhang S, Broxmeyer HE
    Flt3 ligand induces tyrosine phosphorylation of gab1 and gab2 and their association with shp-2, grb2, and PI3 kinase. Biochemical and biophysical research communications 2000 Oct 14;277(1):195-9
  8. 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. Journal of leukocyte biology 1999 Mar;65(3):372-80
  9. Markovic A, MacKenzie KL, Lock RB
    FLT-3: a new focus in the understanding of acute leukemia. The international journal of biochemistry & cell biology 2005 Jun;37(6):1168-72
  10. Hartman AD, Wilson-Weekes A, Suvannasankha A, Burgess GS, Phillips CA, Hincher KJ, Cripe LD, Boswell HS
    Constitutive c-jun N-terminal kinase activity in acute myeloid leukemia derives from Flt3 and affects survival and proliferation. Experimental hematology 2006 Oct;34(10):1360-76
  11. Minami Y, Yamamoto K, Kiyoi H, Ueda R, Saito H, Naoe T
    Different antiapoptotic pathways between wild-type and mutated FLT3: insights into therapeutic targets in leukemia. Blood 2003 Oct 15;102(8):2969-75
  12. Zhang S, Fukuda S, Lee Y, Hangoc G, Cooper S, Spolski R, Leonard WJ, Broxmeyer HE
    Essential role of signal transducer and activator of transcription (Stat)5a but not Stat5b for Flt3-dependent signaling. The Journal of experimental medicine 2000 Sep 4;192(5):719-28
  13. Martelli AM, Faenza I, Billi AM, Manzoli L, Evangelisti C, Fala F, Cocco L
    Intranuclear 3'-phosphoinositide metabolism and Akt signaling: new mechanisms for tumorigenesis and protection against apoptosis? Cellular signalling 2006 Aug;18(8):1101-7
  14. Das B, Shu X, Day GJ, Han J, Krishna UM, Falck JR, Broek D
    Control of intramolecular interactions between the pleckstrin homology and Dbl homology domains of Vav and Sos1 regulates Rac binding. The Journal of biological chemistry 2000 May 19;275(20):15074-81
  15. Heo J, Thapar R, Campbell SL
    Recognition and activation of Rho GTPases by Vav1 and Vav2 guanine nucleotide exchange factors. Biochemistry 2005 May 3;44(17):6573-85
  16. Minden A, Lin A, Claret FX, Abo A, Karin M
    Selective activation of the JNK signaling cascade and c-Jun transcriptional activity by the small GTPases Rac and Cdc42Hs. Cell 1995 Jun 30;81(7):1147-57
  17. Yu C, Minemoto Y, Zhang J, Liu J, Tang F, Bui TN, Xiang J, Lin A
    JNK suppresses apoptosis via phosphorylation of the proapoptotic Bcl-2 family protein BAD. Molecular cell 2004 Feb 13;13(3):329-40
  18. Takeuchi K, Motoda Y, Ito F
    Role of transcription factor activator protein 1 (AP1) in epidermal growth factor-mediated protection against apoptosis induced by a DNA-damaging agent. The FEBS journal 2006 Aug;273(16):3743-55
  19. Eisenmann KM, VanBrocklin MW, Staffend NA, Kitchen SM, Koo HM
    Mitogen-activated protein kinase pathway-dependent tumor-specific survival signaling in melanoma cells through inactivation of the proapoptotic protein bad. Cancer research 2003 Dec 1;63(23):8330-7