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  • Title: The GTP-binding protein Rac does not couple PI 3-kinase to insulin-stimulated glucose transport in adipocytes.
    Author: Marcusohn J, Isakoff SJ, Rose E, Symons M, Skolnik EY.
    Journal: Curr Biol; 1995 Nov 01; 5(11):1296-302. PubMed ID: 8574587.
    Abstract:
    BACKGROUND: In insulin-sensitive cells, such as adipocytes and skeletal muscle, the activation of phosphoinositide 3-kinase (PI 3-kinase) is thought to be critical in allowing insulin to stimulate both the uptake of glucose and the translocation of a specialized glucose transporter, GLUT4, to the plasma membrane. However, the downstream mediators that couple PI 3-kinase to GLUT4 translocation are still not known. Recent studies have shown that the GTP-binding protein Rac mediates some of the biological effects of PI 3-kinase, and these findings have led to the suggestion that Rac may be a common mediator for a variety of responses mediated by PI 3-kinase. To determine whether Rac couples PI 3-kinase to glucose uptake in adipocytes, we produced 3T3-L1 cells expressing either a constitutively active Rac1 (V12 Rac1, containing a valine residue at position 12) or a dominant-inhibitory Rac1 (N17 Rac1, containing an asparagine residue at position 17). RESULTS: The stable expression of both V12 Rac1 and N17 Rac1 led to observable phenotypes in 3T3-L1 cells; expression of V12 Rac1 resulted in constitutive formation of lamellipodia and constitutive activation of the cJun-N-terminal kinase (JNK), whereas expression of N17 Rac1 inhibited the insulin-stimulated formation of lamellipodia. However, neither basal glucose uptake nor insulin-stimulated glucose uptake was affected by the expression of either mutant Rac protein. In addition, expression of V12 Rac1 did not reverse the inhibition of insulin-stimulated glucose uptake caused by the PI 3-kinase inhibitor wortmannin. CONCLUSIONS: These findings provide direct evidence that PI 3-kinase does not use Rac to couple the insulin receptor to glucose uptake in adipocytes. Furthermore, the finding that Rac does not mediate glucose uptake in response to insulin is consistent with the idea that PI 3-kinase couples to a variety of different effector molecules in cells, and suggests that some of the specificity in the biological responses elicited by PI 3-kinase may be mediated by the activation of different effector molecules.
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