Regulation of Rab-GTPase activating proteins, TBC1D1 and TBC1D4
PhD thesis by Jonas Thue Treebak
2009, 150 pages, DKR 100,-
ISBN: 978 87 917 71 224
Delineating the pathways involved in Insulin-dependent and -independent signaling to glucose uptake in GLUT4 expressing tissues is of great importance in order to be able to understand the etiology of diseases in which sensitivity to insulin is diminished. TBC1D1 and TBC1D4 are Rab GTPase-activating proteins known to be involved in GLUT4 mobilization to the plasma membrane in cell culture systems and intact skeletal muscle. Both proteins are believed to be direct down-stream targets of Akt in the insulin signaling cascade. Recently, skeletal muscle contraction and the AMP-activated protein kinase (AMPK) activator, AICAR, were shown also to result in phosphorylation of TBC1D4, indicating that signals activating AMPK resulting in increased glucose uptake could be mediated through TBC1D4.
The work presented here has extended these observations by investigating the involvement of AMPK in the regulation of TBC1D1 and TBC1D4 phosphorylation using AMPK transgenic mouse models. Furthermore, we have applied human exercise models to investigate the phosphorylation pattern of TBC1D4 in response to different exercise intensities and in the post exercise period.
Our data are in line with the idea that TBC1D1 and TBC1D4 are multi-kinase substrates and points of convergence for insulin-dependent and -independent signaling pathways. In addition to experimental data, the present thesis provides a thorough review of the literature describing how TBC1D1 and TBC1D4 are regulated. Finally, future directions are suggested to push forward this exciting area of research.
Contents (pdf, 30 KB)
Summary (pdf, 28 KB)
Preface (pdf, 28 KB)