Abstract
BackgroundTC10 is a small GTPase found in lipid raft microdomains of adipocytes. The protein undergoes activation in response to insulin, and plays a key role in the regulation of glucose uptake by the hormone.Methodology/Principal FindingsTC10 requires high concentrations of magnesium in order to stabilize guanine nucleotide binding. Kinetic analysis of this process revealed that magnesium acutely decreased the nucleotide release and exchange rates of TC10, suggesting that the G protein may behave as a rapidly exchanging, and therefore active protein in vivo. However, in adipocytes, the activity of TC10 is not constitutive, indicating that mechanisms must exist to maintain the G protein in a low activity state in untreated cells. Thus, we searched for proteins that might bind to and stabilize TC10 in the inactive state. We found that Caveolin interacts with TC10 only when GDP-bound and stabilizes GDP binding. Moreover, knockdown of Caveolin 1 in 3T3-L1 adipocytes increased the basal activity state of TC10.Conclusions/SignificanceTogether these data suggest that TC10 is intrinsically active in vivo, but is maintained in the inactive state by binding to Caveolin 1 in 3T3-L1 adipocytes under basal conditions, permitting its activation by insulin.
Highlights
TC10 is a Rho family GTPase, most similar in primary sequence and structure to Cdc42 and TC10b or TCL
Cdc42 was able to bind the nucleotide in both cases; whereas TC10 exhibited a strict requirement for supplemental Mg ions (Figure 1A)
Magnesium is involved in stabilization of nucleotides for most GTPases [25]
Summary
TC10 is a Rho family GTPase, most similar in primary sequence and structure to Cdc and TC10b or TCL. This protein is expressed in a wide variety of tissues, but its role is best studied in adipocytes. TC10 is activated in response to insulin in a CAP-dependent process [3]. Once activated, it binds to several effector proteins including CIP4 [4,5], Exo70 [6,7] and Par6B [8]. The protein undergoes activation in response to insulin, and plays a key role in the regulation of glucose uptake by the hormone
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