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. IntroductionALK-positive anaplastic large-cell lymphomas (ALCLs) are characterized by the expression of a hybrid protein, associating the cytoplasmic portion of the ALK tyrosine kinase (anaplastic lymphoma kinase) with a partner protein. This hybrid kinase is often encoded by the NPM-ALK fusion gene resulting from the (2;5)(p23; q35) chromosomal translocation. However, several reports have shown that the ALK gene at 2p23 may also be involved in a number of variant translocations. 1,2 The dimerization of NPM-ALK through NPM mimics ligand binding and leads to the constitutive activation of the ALK tyrosine kinase through tyrosine transphosphorylation and autophosphorylation. 3,4 Phosphorylated NPM-ALK promotes cell survival and tumorigenesis through the activation of multiple SH2-domain-containing proteins, including the phospholipase C ␥1 (PLC␥1), PI-3Kinase/AKT, and the JAK/STAT pathways, that control cell-cycle progression. [5][6][7][8][9][10][11] It is likely that the oncogenic potential of NPM-ALK may be related with its kinase capability and consequently its tyrosine phosphorylation level. 1,12 As previously reported, pp60c-src of the Src-family kinases interacts with NPM-ALK, participates in its phosphorylation, and could be an important actor in NPM-ALK-mediated mitogenicity. 13 Although the mechanism of NPM-ALK activation is well documented, the downregulation process is totally unknown.Phosphorylation of proteins on tyrosine residues is regulated by the activities of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). Deregulation of the balance that exists between these 2 groups of enzymes can trigger the accumulation of tyrosine-phosphorylated proteins, which, in turn, can lead to abnormal cell proliferation and tumorigenesis. Two SH2-domaincontaining phosphotyrosine phosphatases, SHP1 and SHP2, are widely implicated in the regulation of signaling pathways involved in cell proliferation, differentiation, and survival. 14 It is well established that these 2 PTPs are involved in the pathogenesis of lymphoma, leukemia, and other types of cancers. 15,16 Despite their high degree of homology, SHP1 and SHP2 have completely distinct expression profiles and functions. In contr...