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Comment
. 2007 Apr 15;403(2):e9-11.
doi: 10.1042/BJ20070271.

Thrifty Tbc1d1 and Tbc1d4 proteins link signalling and membrane trafficking pathways

Françoise Koumanov  1 , Geoffrey D Holman
Affiliations
Comment

Thrifty Tbc1d1 and Tbc1d4 proteins link signalling and membrane trafficking pathways

Françoise Koumanov et al. Biochem J. .

Abstract

Establishing a complete pathway which links occupancy of the insulin receptor to GLUT4 translocation has been particularly elusive because of the complexities involved in studying both signalling and membrane trafficking processes. However, Lienhard's group has now discovered two related molecules that could function in this linking role. These proteins, Tbc1d4 (also known as AS160) and now Tbc1d1, as reported in this issue of the Biochemical Journal, have been demonstrated to be Rab GAPs (GTPase-activating proteins) that link upstream to Akt (protein kinase B) and phosphoinositide 3-kinase and downstream to Rabs involved in trafficking of GLUT4 vesicles. The data from Leinhard and colleagues suggest that high levels of Rab GAP activity lead to suppression of GLUT4 translocation and this observation has wide significance and is likely to be relevant to the recent discovery that mutations in the Tbc1d1 gene lead to some cases of severe human obesity.

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Figures

Figure 1
Figure 1. Lienhard's hypothesis for a role of the Tbc1d1 and Tbc1d4 proteins as links between insulin signalling and GLUT4 vesicle trafficking
Insulin leads to autophosphorylation of its receptor which in turn leads to tyrosine phosphorylation of IRS1. This couples to activation of PI 3-kinase (phosphoinositide 3-kinase) which produces PIP3 (phosphatidylinositol trisphosphate) in the plasma membrane. PDK1, PDK2 and Akt become associated with PIP3 and together lead to the phosphorylation and activation of Akt. Activated Akt then phosphorylates Tbc1d1 and Tbc1d4 and this leads to suppression of their GTPase-activating activity. This may occur directly or indirectly through association of the phosphorylated proteins (Rab-GAP-p) with 14-3-3 and relocation to the cytoplasm. Following the reduction in GLUT4-vesicle-associated Rab GAP activity, the vesicle-associated Rabs are converted into their active GTP-loaded forms and this switch facilitates trafficking of the vesicles to the plasma membrane and possibly enhanced docking at the plasma membrane.
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