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ABSTRACT The FLT3 receptor tyrosine kinase and its ligand, FL, regulate the development of hematopoietic stem cells and early B lymphoid progenitors. FL has a strong capacity to boost

production of dendritic and natural killer cells _in vivo_, thereby providing a new and promising tool for anti-cancer immunotherapy. Intracellular FLT3 signaling involves tyrosine

phosphorylation of several cytoplasmic proteins including SHC. We have found that upon FLT3 activation SHC phosphorylation occurs at tyrosine 239/240 and 313. SHC possesses two

phosphotyrosine-binding domains: an amino-terminal phosphotyrosine binding (PTB) and a carboxy-terminal Src Homology 2 (SH2) domain. Neither is required for SHC phosphorylation, but the PTB

domain is necessary and sufficient for SHC binding to the SH2 containing inositol phosphatase (SHIP). Overexpression of SHC increases the level of SHIP phosphorylation on tyrosines in

response to FLT3 activation, suggesting that SHC availability is a limiting step for SHIP phosphorylation. This effect is observed only if the SHC PTB domain is functional. Interestingly,

SHC overexpression in FLT3-activatable Ba/F3 cells limits FLT3-dependent cell growth and this effect requires tyrosine 313. Taken together, the present data show that SHC can antagonize cell

proliferation induced by FLT3 stimulation and regulate phosphorylation of the SHIP negative regulator. In addition, our study provides the structural bases for SHC phosphorylation and

formation of the SHC/SHIP complex. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS Access through your

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FGR AND HCK ENHANCES THE TUMOR BURDEN OF ACUTE MYELOID LEUKEMIA CELLS IN IMMUNOCOMPROMISED MICE Article Open access 02 January 2025 AUTHOR INFORMATION Author notes * O Rosnet Present

address: Centre d’Immunologie de Marseille-Luminy, Marseille, France AUTHORS AND AFFILIATIONS * Laboratoire d’Oncologie Moléculaire, Institut Paoli-Calmettes, Marseille, France S Marchetto, 

E Fournier, J-P Borg, D Birnbaum & O Rosnet * Laboratoire d’Hématologie Moléculaire et Fonctionnelle, INSERM U119, Institut Paoli-Calmettes, Marseille, France N Beslu & P Dubreuil *

Laboratoire de Biologie Cellulaire, Institut Paoli-Calmettes, Marseille, France T Aurran-Schleinitz Authors * S Marchetto View author publications You can also search for this author

inPubMed Google Scholar * E Fournier View author publications You can also search for this author inPubMed Google Scholar * N Beslu View author publications You can also search for this

author inPubMed Google Scholar * T Aurran-Schleinitz View author publications You can also search for this author inPubMed Google Scholar * P Dubreuil View author publications You can also

search for this author inPubMed Google Scholar * J-P Borg View author publications You can also search for this author inPubMed Google Scholar * D Birnbaum View author publications You can

also search for this author inPubMed Google Scholar * O Rosnet View author publications You can also search for this author inPubMed Google Scholar RIGHTS AND PERMISSIONS Reprints and

permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Marchetto, S., Fournier, E., Beslu, N. _et al._ SHC and SHIP phosphorylation and interaction in response to activation of the FLT3 receptor.

_Leukemia_ 13, 1374–1382 (1999). https://doi.org/10.1038/sj.leu.2401527 Download citation * Received: 07 April 1999 * Accepted: 04 June 1999 * Published: 09 September 1999 * Issue Date: 01

September 1999 * DOI: https://doi.org/10.1038/sj.leu.2401527 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a

shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * FLT3 * SHC * SHIP *

phosphotyrosine * SH2 domain * PTB domain