SHP1 tyrosine phosphatase negatively regulates NPM-ALK tyrosine kinase signaling

Honorat, Jean-François; Ragab, Ashraf; Lamant, Laurence; Delsol, Georges; Ragab-Thomas, Jeannie M.F.

doi:10.1182/blood-2005-06-2421

Cited by 47 publications

(50 citation statements)

References 44 publications

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“…Lastly, after we submitted this manuscript for publication, Honorat et al 45 have published that NPM-ALK is a substrate for SHP1, and SHP1 negatively regulates NPM-ALK and decreases tumorigenecity. Thus, these findings are in keeping with the concept that loss of SHP1 contributes to the pathogenesis of ALK þ ALCL.…”

Section: Discussionmentioning

confidence: 99%

Restoration of shp1 expression by 5-AZA-2′-deoxycytidine is associated with downregulation of JAK3/STAT3 signaling in ALK-positive anaplastic large cell lymphoma

et al. 2006

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Anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALK þ ALCL) is characterized by constitutive activation of the Janus kinase (JAK)3/signal transducers and activators of transcription 3 (STAT3) signaling pathway. SHP1, a tyrosine phosphatase that negatively regulates JAK/STAT, is frequently absent in ALK þ ALCL owing to gene methylation. To test the hypothesis that loss of SHP1 contributes to JAK3/ STAT3 activation in ALK þ ALCL cells, we induced SHP1 expression using 5-aza-2 0 -deoxycytidine (5-AZA), an inhibitor of DNA methyltransferase, in ALK þ ALCL cell lines, and correlated with changes in the JAK3/STAT3 pathway. 5-AZA gradually restored SHP1 expression in Karpas 299 and SU-DHL-1 cells over 5 days. The initially low level of SHP1 expression did not result in significant changes to the expression or tyrosine phosphorylation of JAK3 and STAT3. However, higher levels of SHP1 seen subsequently correlated with substantial decreases in JAK3 and pJAK3, followed by pSTAT3 (but not STAT3). Importantly, the decrease in JAK3 was abrogated by MG132, a proteasome inhibitor. 5-AZA induced no significant increase in apoptosis but it sensitized ALCL cells to doxorubicin-induced apoptosis. Our findings support the concept that loss of SHP1 contributes to the constitutive activation of JAK3/STAT3 in ALK þ ALCL cells. SHP1 appears to downregulate JAK3 by two mechanisms: tyrosine dephosphorylation and increased degradation via the proteasome pathway.

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Section: Discussionmentioning

confidence: 99%

Restoration of shp1 expression by 5-AZA-2′-deoxycytidine is associated with downregulation of JAK3/STAT3 signaling in ALK-positive anaplastic large cell lymphoma

et al. 2006

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“…Pro-mitogenic functions include binding of adaptors, such as Shc, Grb2 and IRS1, to regulators of the Erk pathway, phospholipase Cg (PLCg), tyrosine phosphatases and the protooncogene pp60 c-src (Fujimoto et al, 1996;Bai et al, 1998;Cussac et al, 2004;Honorat et al, 2006;Marzec et al, 2007). Antiapoptotic functions are related to the activation of the survival phosphatidylinositol 3-kinase (PI3K)/AKT pathway and of the Jak/STAT3-5 module (Bai et al, 2000;Amin et al, 2003;Chiarle et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Activation of Rac1 and the exchange factor Vav3 are involved in NPM-ALK signaling in anaplastic large cell lymphomas

et al. 2007

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The majority of anaplastic large cell lymphomas (ALCLs) express the nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) fusion protein, which is oncogenic due to its constitutive tyrosine kinase activity. Transformation by NPM-ALK not only increases proliferation, but also modifies cell shape and motility in both lymphoid and fibroblastic cells. We report that the Rac1 GTPase, a known cytoskeletal regulator, is activated by NPM-ALK in ALCL cell lines (Karpas 299 and Cost) and transfected cells (lymphoid Ba/F3 cells, NIH-3T3 fibroblasts). We have identified Vav3 as one of the exchange factors involved in Rac1 activation. Stimulation of Vav3 and Rac1 by NPM-ALK is under the control of Src kinases. It involves formation of a signaling complex between NPM-ALK, pp60 c-src , Lyn and Vav3, in which Vav3 associates with tyrosine 343 of NPM-ALK via its SH2 domain. Moreover, Vav3 is phosphorylated in NPM-ALK positive biopsies from patients suffering from ALCL, demonstrating the pathological relevance of this observation. The use of Vav3-specific shRNA and a dominant negative Rac1 mutant demonstrates the central role of GTPases in NPM-ALK elicited motility and invasion.

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“…61 Shp1 also has direct inhibitory effects on NPM-ALK via dephosphorylation of this protein. 62 Loss of Shp1 expression is a relatively common defect in hematologic malignancies. 63 In a series of ALK ϩ ALCL tumors derived from children and adult patients, Shp1 expression was lost in 50% and 86% of the tumors, respectively.…”

Section: Jak/statmentioning

confidence: 99%

Pathobiology of ALK+ anaplastic large-cell lymphoma

Amin

Lai

2007

Blood

236

173

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Anaplastic large-cell lymphoma (ALCL) was initially recognized on the basis of morphologic features and the consistent expression of CD30. It then became evident that the majority of these tumors are derived from lymphoid cells of T or null immunophenotype. The subsequent finding that t(2;5)(p23;q35) occurs in 40% to 60% of ALCL patients established a distinct clinicopathologic entity. This chromosomal translocation induces the formation of the chimeric protein nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), which possesses significant oncogenic potential resulting from the constitutive activation of the tyrosine kinase ALK. In addition to its specific pathophysiologic events, NPM-ALKexpressing lymphoma presents with consistent clinical manifestations. Only 13 years after the identification of NPM-ALK, tremendous progress has been made in our understanding of this molecule because of the relentless efforts of multiple investigators who have dissected its biologic roles using in vitro and in vivo experimental models. Several upstream modulators, cross-reacting oncogenes, and downstream effectors of NPM-ALK have been identified and characterized. Understanding these interacting oncogenic systems is expected to facilitate the design of new therapeutic strategies and agents. In this review, we briefly discuss ALCL and focus on NPM-ALK. IntroductionAnaplastic large-cell lymphoma (ALCL) is a relatively uncommon tumor. It was first recognized by Stein et al 1 in 1985, who reported the consistent expression of the Ki-1 antigen (later designated CD30) in tumors with frequent cohesive proliferation of large pleomorphic cells. Most of these tumors were labeled "histiocytic malignancies." 1 The Ki-1 monoclonal antibody was originally described by the same group and was used to identify a novel antigen in the Hodgkin lymphoma cell line L428. 2 Subsequent immunophenotyping and gene rearrangement studies showed that the vast majority of ALCL tumors are derived from lymphoid cells of T or null immunophenotype. 3 Histologically, several ALCL variants have been described. Of these variants, the common, lymphohistiocytic, and small-cell are the most frequently encountered. The "horseshoe" or "wreath" cell is considered the cytologic hallmark of this disease. 4 ALCL occurs as 2 distinct clinical entities, as a widespread systemic disease, or as a localized cutaneous disease. Systemic ALCL comprises 2% to 8% of non-Hodgkin lymphomas in adults and 10% to 15% of these lymphomas in children. 5 The frequency of ALCL increases to 30% to 40% of non-Hodgkin lymphomas in children when only cases with large-cell morphology are included. ALKThe recognition of t(2;5)(p23;q35) established the molecular definition of a subset of ALCL tumors that harbors this translocation. [6][7][8] In 1994, 2 independent groups cloned the genes involved in this translocation and illustrated the fusion of the nucleophosmin (NPM) gene on chromosome 5q35 to the previously unidentified gene anaplastic lymphoma kinase (ALK) gene on 2p23. 9,10 This chromosomal t...

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SHP1 tyrosine phosphatase negatively regulates NPM-ALK tyrosine kinase signaling

Cited by 47 publications

References 44 publications

Restoration of shp1 expression by 5-AZA-2′-deoxycytidine is associated with downregulation of JAK3/STAT3 signaling in ALK-positive anaplastic large cell lymphoma

Restoration of shp1 expression by 5-AZA-2′-deoxycytidine is associated with downregulation of JAK3/STAT3 signaling in ALK-positive anaplastic large cell lymphoma

Activation of Rac1 and the exchange factor Vav3 are involved in NPM-ALK signaling in anaplastic large cell lymphomas

Pathobiology of ALK+ anaplastic large-cell lymphoma

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