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SHP1 tyrosine phosphatase negatively regulates NPM-ALK tyrosine kinase signaling.

Abstract : Anaplastic large-cell lymphoma (ALCL) is frequently associated with the 2;5 translocation and expresses the NPM-ALK fusion protein, which possesses a constitutive tyrosine kinase activity. We analyzed SHP1 tyrosine phosphatase expression and activity in 3 ALK-positive ALCL cell lines (Karpas 299, Cost, and SU-DHL1) and in lymph node biopsies (n = 40). We found an inverse correlation between the level of NPM-ALK phosphorylation and SHP1 phosphatase activity. Pull-down and coimmunoprecipitation experiments demonstrated a SHP1/NPM-ALK association. Furthermore, confocal microscopy performed on ALCL cell lines and biopsy specimens showed the colocalization of the 2 proteins in cytoplasmic bodies containing Y664-phosphorylated NPM-ALK. Dephosphorylation of NPM-ALK by SHP1 demonstrated that NPM-ALK was a SHP1 substrate. Downregulation of SHP1 expression by RNAi in Karpas cells led to hyperphosphorylation of NPM-ALK, STAT3 activation, and increase in cell proliferation. Furthermore, SHP1 overexpression in 3T3 fibroblasts stably expressing NPM-ALK led to the decrease of NPM-ALK phosphorylation, lower cell proliferation, and tumor progression in nude mice. These findings show that SHP1 is a negative regulator of NPM-ALK signaling. The use of tissue microarrays revealed that 50% of ALK-positive ALCLs were positive for SHP1. Our results suggest that SHP1 could be a critical enzyme in ALCL biology and a potential therapeutic target.
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Submitted on : Tuesday, April 3, 2007 - 3:10:36 PM
Last modification on : Monday, July 4, 2022 - 9:09:48 AM



Jean-François Honorat, Ashraf Ragab, Laurence Lamant, Georges Delsol, Jeannie Ragab-Thomas. SHP1 tyrosine phosphatase negatively regulates NPM-ALK tyrosine kinase signaling.. Blood, American Society of Hematology, 2006, 107 (10), pp.4130-8. ⟨10.1182/blood-2005-06-2421⟩. ⟨inserm-00139774⟩



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