SHP2 mediates the protective effect of interleukin-6 against dexamethasone-induced apoptosis in multiple myeloma cells.
Our previous studies have shown that activation of a related adhesion focal tyrosine kinase (RAFTK) (also known as Pyk2) is required for dexamethasone (Dex)-induced apoptosis in multiple myeloma (MM) cells and that human interleukin-6 (IL-6), a known growth and survival factor for MM cells, blocks both RAFTK activation and apoptosis induced by Dex. However, the mechanism whereby IL-6 inhibits Dex-induced apoptosis is undefined. In this study, we demonstrate that protein-tyrosine phosphatase SHP2 mediates this protective effect. We show that IL-6 triggers selective activation of SHP2 and its association with RAFTK in Dex-treated MM cells. SHP2 interacts with RAFTK through a region other than its Src homology 2 domains. We demonstrate that RAFTK is a direct substrate of SHP2 both in vitro and in vivo, and that Tyr(906) in the C-terminal domain of RAFTK mediates its interaction with SHP2. Moreover, overexpression of dominant negative SHP2 blocked the protective effect of IL-6 against Dex-induced apoptosis. These findings demonstrate that SHP2 mediates the anti-apoptotic effect of IL-6 and suggest SHP2 as a novel therapeutic target in MM.
Chauhan
D
D
Department of Adult Oncology, Dana-Farber Cancer Institute, Division of Experimental Medicine and Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine and Harvard Medical School, Boston, Massachusetts 02115, USA.
Pandey
P
P
Hideshima
T
T
Treon
S
S
Raje
N
N
Davies
F E
FE
Shima
Y
Y
Tai
Y T
YT
Rosen
S
S
Avraham
S
S
Kharbanda
S
S
Anderson
K C
KC
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D003907:Dexamethasone / Q000494:pharmacology*; D051418:Focal Adhesion Kinase 2; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins; D007700:Kinetics; D009101:Multiple Myeloma; D010766:Phosphorylation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases; D014162:Transfection; D014407:Tumor Cells, Cultured; D018909:src Homology Domains
D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D011994:Recombinant Proteins; D003907:Dexamethasone; D011505:Protein-Tyrosine Kinases; D051418:Focal Adhesion Kinase 2; C516724:PTPN11 protein, human; C509249:PTPN6 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases