scholarly journals Suppression of PDGF-induced PI3 kinase activity by imatinib promotes adipogenesis and adiponectin secretion

2012 ◽  
Vol 48 (3) ◽  
pp. 229-240 ◽  
Author(s):  
Stephen Fitter ◽  
Kate Vandyke ◽  
Stan Gronthos ◽  
Andrew C W Zannettino

Improved glucose and lipid metabolism is a unique side effect of imatinib therapy in some chronic myeloid leukaemia (CML) patients. We recently reported that plasma levels of adiponectin, an important regulator of insulin sensitivity, are elevated following imatinib therapy in CML patients, which could account for these improved metabolic outcomes. Adiponectin is secreted exclusively from adipocytes, suggesting that imatinib modulates adiponectin levels directly, by transcriptional upregulation of adiponectin in pre-existing adipocytes, and/or indirectly, by stimulating adipogenesis. In this report, we have demonstrated that imatinib promotes adipogenic differentiation of human mesenchymal stromal cells (MSCs), which in turn secrete high-molecular-weight adiponectin. Conversely, imatinib does not stimulate adiponectin secretion from mature adipocytes. We hypothesise that inhibition of PDGFRα (PDGFRA) and PDGFRβ (PDGFRB) is the mechanism by which imatinib promotes adipogenesis. Supporting this, functional blocking antibodies to PDGFR promote adipogenesis and adiponectin secretion in MSC cultures. We have shown that imatinib is a potent inhibitor of PDGF-induced PI3 kinase activation and, using a PI3 kinase p110α-specific inhibitor (PIK-75), we have demonstrated that suppression of this pathway recapitulates the effects of imatinib on MSC differentiation. Furthermore, using mitogens that activate the PI3 kinase pathway, or MSCs expressing constitutively activated Akt, we have shown that activation of the PI3 kinase pathway negates the pro-adipogenic effects of imatinib. Taken together, our results suggest that imatinib increases plasma adiponectin levels by promoting adipogenesis through the suppression of PI3 kinase signalling downstream of PDGFR.

Blood ◽  
1998 ◽  
Vol 91 (1) ◽  
pp. 46-53 ◽  
Author(s):  
Hiroo Ueno ◽  
Ko Sasaki ◽  
Hiroaki Honda ◽  
Tetsuya Nakamoto ◽  
Tetsuya Yamagata ◽  
...  

Interleukin-4 (IL-4) is a cytokine that induces both proliferation and differentiation and suppresses apoptosis of B cells. Although IL-4 has been shown to activate the phosphatidylinositol 3′ (PI3)-kinase pathway, the role of PI3 kinase in the IL-4 receptor (IL-4R) signaling remains unclear. In this study, we demonstrated that c-Cbl proto-oncogene product is inducibly phosphorylated on tyrosine residues and is associated with the p85 subunit of PI3-kinase by IL-4 stimulation. Overexpression of c-Cbl enhances the PI3-kinase activity and, at the same time, mitogenic activity and survival of cells in the presence of IL-4. However, these effects of c-Cbl were abolished by wortmannin, a specific inhibitor for the PI3 kinase pathway, or by a point mutation at tyrosine 731 of c-Cbl, which is a major binding site for p85. These results indicate that c-Cbl plays a role in linking IL-4R with the PI3 kinase pathway and thus enhancing the mitogenic and survival signals.


Blood ◽  
1998 ◽  
Vol 91 (1) ◽  
pp. 46-53 ◽  
Author(s):  
Hiroo Ueno ◽  
Ko Sasaki ◽  
Hiroaki Honda ◽  
Tetsuya Nakamoto ◽  
Tetsuya Yamagata ◽  
...  

Abstract Interleukin-4 (IL-4) is a cytokine that induces both proliferation and differentiation and suppresses apoptosis of B cells. Although IL-4 has been shown to activate the phosphatidylinositol 3′ (PI3)-kinase pathway, the role of PI3 kinase in the IL-4 receptor (IL-4R) signaling remains unclear. In this study, we demonstrated that c-Cbl proto-oncogene product is inducibly phosphorylated on tyrosine residues and is associated with the p85 subunit of PI3-kinase by IL-4 stimulation. Overexpression of c-Cbl enhances the PI3-kinase activity and, at the same time, mitogenic activity and survival of cells in the presence of IL-4. However, these effects of c-Cbl were abolished by wortmannin, a specific inhibitor for the PI3 kinase pathway, or by a point mutation at tyrosine 731 of c-Cbl, which is a major binding site for p85. These results indicate that c-Cbl plays a role in linking IL-4R with the PI3 kinase pathway and thus enhancing the mitogenic and survival signals.


2006 ◽  
Vol 114 (08) ◽  
Author(s):  
T Colaco ◽  
C Onofri ◽  
M Theodoropoulou ◽  
M Kowarik ◽  
GK Stalla ◽  
...  

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Rajani Kanteti ◽  
Jacob J. Riehm ◽  
Immanuel Dhanasingh ◽  
Frances E. Lennon ◽  
Tamara Mirzapoiazova ◽  
...  

2016 ◽  
Vol 15 (1) ◽  
Author(s):  
Zahid Nawaz ◽  
Vikas Patil ◽  
Yashna Paul ◽  
Alangar S. Hegde ◽  
Arimappamagan Arivazhagan ◽  
...  

2008 ◽  
Vol 44 (4) ◽  
pp. 752-753
Author(s):  
Edwin A. Garcia ◽  
Gaelle Kikonda Kanda ◽  
Alexander Lyon ◽  
Clare E. Gallon ◽  
Andrew E. Messer ◽  
...  

2009 ◽  
Vol 41 (5) ◽  
pp. 524-526 ◽  
Author(s):  
Jennifer C King ◽  
Jin Xu ◽  
John Wongvipat ◽  
Haley Hieronymus ◽  
Brett S Carver ◽  
...  

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