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September 1999, Volume 13, Number 9, Pages 1374-1382
Table of contents    Previous  Abstract  Next   Article  PDF
Original manuscript
SHC and SHIP phosphorylation and interaction in response to activation of the FLT3 receptor
S Marchetto1, E Fournier1, N Beslu2, T Aurran-Schleinitz3, P Dubreuil2, J-P Borg1, D Birnbaum1 and O Rosnet1,a

1Laboratoire d'Oncologie Moléculaire, Institut Paoli-Calmettes, Marseille, France

2Laboratoire d'Hématologie Moléculaire et Fonctionnelle, INSERM U119, Institut Paoli-Calmettes, Marseille, France

3Laboratoire de Biologie Cellulaire, Institut Paoli-Calmettes, Marseille, France

Correspondence to: O Rosnet, Centre d'Immunologie de Marseille-Luminy, Parc Scientifique et Technologique de Luminy, Case 906, 13288 Marseille Cedex 09, France; Fax: 33 4 91 26 94 30

aPresent address: Centre d'Immunologie de Marseille-Luminy, Marseille, France

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.

Keywords

FLT3; SHC; SHIP; phosphotyrosine; SH2 domain; PTB domain

Received 7 April 1999; accepted 4 June 1999
September 1999, Volume 13, Number 9, Pages 1374-1382
Table of contents    Previous  Abstract  Next   Article  PDF