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Blood, 15 October 2006, Vol. 108, No. 8, pp. 2796-2803. Prepublished online as a Blood First Edition Paper on July 6, 2006; DOI 10.1182/blood-2006-04-017434. This Article Full Text (PDF) All Versions of this Article: blood-2006-04-017434v1 108/8/2796    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Han, Y. Articles by Lai, R. Search for Related Content PubMed PubMed Citation Articles by Han, Y. Articles by Lai, R. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted April 14, 2006 Accepted June 14, 2006 Loss of SHP1 enhances JAK3/STAT3 signaling and decreases proteosome degradation of JAK3 and NPM-ALK in ALK-positive anaplastic large-cell lymphoma Yajun Han, Hesham Amin, Bevin Franko, Christine Frantz, Xinzhe Shi, and Raymond Lai* Department of Laboratory Medicine and Pathology, U of Alberta Department of Hematopathology, MD Anderson Cancer Center * Corresponding author; email: raymondmail_65{at}yahoo.com. Previous studies showed that most cases of ALK-positive anaplastic large cell lymphoma (ALK+ALCL) do not express SHP1, a tyrosine phosphatase and an important negative regulator for cellular signaling pathways such as that of JAK/STAT. To fully assess the biological significance of loss of SHP1 in ALK+ALCL, we transfected SHP1 plasmids into two SHP1-negative, ALK+ALCL cell lines, Karpas 299 and SU-DHL-1. After 24 hours of transfection, pJAK3 and pSTAT3 were decreased, and these changes correlated with downregulation of STAT3 downstream targets including cyclin D3, mcl-1 and bcl-2. Expression of SHP1 in these two cell lines also resulted in marked decreases in the protein levels of JAK3 and NPM-ALK, and these effects were reversible by proteosome inhibitor MG132. Conversely, when SHP1 expression in SUP-M2 (a SHP1-positive ALK+ALCL cell line) was inhibited using siRNA, pSTAT3, pJAK3, JAK3 and NPM-ALK were all upregulated. Co-immunoprecipitation studies showed that SHP1 was physically associated with JAK3 and NPM-ALK. SHP1 expression in Karpas 299 and SU-DHL-1 led to significant G1 cell-cycle arrest but not apoptosis. To conclude, loss of SHP1 contributes to the pathogenesis of ALK+ALCL by two mechanisms: 1) leaves the tyrosine phosphorylation and activation of JAK3/STAT3 unchecked, and 2) decreases proteosome degradation of JAK3 and NPM- ALK. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: ALK-mediated oncogenesis: mechanisms that matter Stephan W. Morris Blood 2006 108: 2500-2501. [Full Text] [PDF] This article has been cited by other articles: J. Dien Bard, P. Gelebart, M. Anand, Z. Zak, S. A. Hegazy, H. M. Amin, and R. Lai IL-21 Contributes to JAK3/STAT3 Activation and Promotes Cell Growth in ALK-Positive Anaplastic Large Cell Lymphoma Am. J. Pathol., August 1, 2009; 175(2): 825 - 834. [Abstract] [Full Text] [PDF] M. K. Pandey, B. Sung, K. S. Ahn, and B. B. Aggarwal Butein Suppresses Constitutive and Inducible Signal Transducer and Activator of Transcription (STAT) 3 Activation and STAT3-Regulated Gene Products through the Induction of a Protein Tyrosine Phosphatase SHP-1 Mol. Pharmacol., March 1, 2009; 75(3): 525 - 533. [Abstract] [Full Text] [PDF] F. Wu, P. Wang, L. C. Young, R. Lai, and L. Li Proteome-Wide Identification of Novel Binding Partners to the Oncogenic Fusion Gene Protein, NPM-ALK, using Tandem Affinity Purification and Mass Spectrometry Am. J. Pathol., February 1, 2009; 174(2): 361 - 370. [Abstract] [Full Text] [PDF] A. B. Kunnumakkara, A. S. Nair, B. Sung, M. K. Pandey, and B. B. Aggarwal Boswellic Acid Blocks Signal Transducers and Activators of Transcription 3 Signaling, Proliferation, and Survival of Multiple Myeloma via the Protein Tyrosine Phosphatase SHP-1 Mol. Cancer Res., January 1, 2009; 7(1): 118 - 128. [Abstract] [Full Text] [PDF] K. S. Ahn, G. Sethi, B. Sung, A. Goel, R. Ralhan, and B. B. Aggarwal Guggulsterone, a Farnesoid X Receptor Antagonist, Inhibits Constitutive and Inducible STAT3 Activation through Induction of a Protein Tyrosine Phosphatase SHP-1 Cancer Res., June 1, 2008; 68(11): 4406 - 4415. [Abstract] [Full Text] [PDF] H. M. Amin and R. Lai Pathobiology of ALK+ anaplastic large-cell lymphoma Blood, October 1, 2007; 110(7): 2259 - 2267. [Abstract] [Full Text] [PDF] A. K. Pathak, M. Bhutani, A. S. Nair, K. S. Ahn, A. Chakraborty, H. Kadara, S. Guha, G. Sethi, and B. B. Aggarwal Ursolic Acid Inhibits STAT3 Activation Pathway Leading to Suppression of Proliferation and Chemosensitization of Human Multiple Myeloma Cells Mol. Cancer Res., September 1, 2007; 5(9): 943 - 955. [Abstract] [Full Text] [PDF] H M Kocher, L Mears, N C Lea, K Raj, and G J Mufti JAK V617F missense mutation is absent in pancreatic cancer Gut, August 1, 2007; 56(8): 1174 - 1175. [Full Text] [PDF] M. Bhutani, A. K. Pathak, A. S. Nair, A. B. Kunnumakkara, S. Guha, G. Sethi, and B. B. Aggarwal Capsaicin Is a Novel Blocker of Constitutive and Interleukin-6-Inducible STAT3 Activation Clin. Cancer Res., May 15, 2007; 13(10): 3024 - 3032. [Abstract] [Full Text] [PDF]

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