TY - JOUR
T1 - Loss of SHP1 enhances JAK3/STAT3 signaling and decreases proteosome degradation of JAK3 and NPM-ALK in ALK+ anaplastic large-cell lymphoma
AU - Han, Yajun
AU - Amin, Hesham M.
AU - Franko, Bevin
AU - Frantz, Christine
AU - Shi, Xinzhe
AU - Lai, Raymond
PY - 2006/10/15
Y1 - 2006/10/15
N2 - Previous studies showed that most cases of ALK+ 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 biologic significance of loss of SHP1 in ALK+ALCL, we transfected SHP1 plasmids into 2 SHP1 -, 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 down-regulation of STAT3 downstream targets including cyclin D3, mcl-1, and bcl-2. Expression of SHP1 in these 2 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+ ALK+ALCL cell line) was inhibited using siRNA, pSTAT3, pJAK3, JAK3, and NPM-ALK were all up-regulated. Coimmunoprecipitation 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 2 mechanisms: (1) it leaves the tyrosine phosphorylation and activation of JAK3/STAT3 unchecked and (2) it decreases proteosome degradation of JAK3 and NPM-ALK.
AB - Previous studies showed that most cases of ALK+ 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 biologic significance of loss of SHP1 in ALK+ALCL, we transfected SHP1 plasmids into 2 SHP1 -, 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 down-regulation of STAT3 downstream targets including cyclin D3, mcl-1, and bcl-2. Expression of SHP1 in these 2 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+ ALK+ALCL cell line) was inhibited using siRNA, pSTAT3, pJAK3, JAK3, and NPM-ALK were all up-regulated. Coimmunoprecipitation 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 2 mechanisms: (1) it leaves the tyrosine phosphorylation and activation of JAK3/STAT3 unchecked and (2) it decreases proteosome degradation of JAK3 and NPM-ALK.
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U2 - 10.1182/blood-2006-04-017434
DO - 10.1182/blood-2006-04-017434
M3 - Article
C2 - 16825495
AN - SCOPUS:33750632572
SN - 0006-4971
VL - 108
SP - 2796
EP - 2803
JO - Blood
JF - Blood
IS - 8
ER -