Ultrastructural and biochemical analyses have implicated the actin cytoskeleton as having a role in caveolae function [21-24]. Caveolin is also involved in dynamic actin remodeling in endocytosis or molecular trafficking.
In adipocytes, the stimulation of glucose uptake by insulin is achieved via the translocation of intracellular glucose transporter 4 (GLUT4) to the cell-surface membrane. Insulin-induced GLUT4 translocation in adipocytes requires dynamic actin remodeling at the inner surface of the plasma membrane (cortical actin) and in the perinuclear region . In particular, the treatment of adipocytes with the actin-depolymerizing agents cytochalasin D and latrunculin A or B, and the actin-stabilizing agent jasplakinolide, all lead to the inhibition of insulin-stimulated GLUT4 translocation [25-29].
Caveolin-1 mediates the translocation of GLUT4 through direct binding with actin filaments in adipocytes. In differentiated adipocytes, the stress fiber F-actin becomes small patches of punctate actin that are co-localized with the caveolin-positive clusters. In adipocytes, caveolin-actin structures are disrupted by mbCD (which in caveolae causes cholesterol depletion) . Taken together, these results suggest that, in adipocytes, caveolin-1 may play an important role in the translocation of GLUT4 through direct binding with actin.
The F-actin cross-linking protein filamin was identified as being a ligand for caveolin-1 by using a yeast two-hybrid screen . The N-terminus of caveolin-1 binds to both nonmuscle and muscle filamin, indicating that such interaction might not be cell type-specific. Caveolin-1 is present in filamin-positive patches at the plasma membrane, and is co-aligned with actin stress fibers upon Rho stimulation. Filamin plays a role in cell locomotion and mechanoprotection, and also as a cytoskeletal linker for transmembrane proteins such as integrins and glycoprotein I complex in platelets. Therefore, the interaction of caveolin-1 with filamin supports one of the possibilities that caveolin-1 is linked to the cortical actin cytoskele-ton via filamin.
Caveolin-1, in addition, can indirectly regulate actin remodeling by the activation of Rho family small GTP-binding protein TC10 upon insulin-stimulation in adipocytes. The translocation of GLUT4 requires both phosphatidylinositol (PI) 3-ki-nase-dependent pathways for activation of Akt [32-34], and a PI3-kinase-independ-ent pathway for the activation of TC10 [35-37]. Recently, both PI3-kinase and TC10 have been reported as being involved in the regulation of actin cytoskeleton rearrangement in various cell types [25,38,39]. TC10 is mainly localized to the caveolae, and subsequently caveolin-1-enriched caveolae are required for the activation of TC10 through a CAP-Cbl signaling pathway [35,36]. Insulin stimulates the phosphorylation of another insulin receptor substrate, the proto-oncogene c-Cbl . Once phosphorylated, Cbl can recruit the SH2-containing adapter protein CrkII to caveolae along with the guanine nucleotide exchange factor C3G. The latter then appears to activate TC10 . Although the action of TC10 remains unknown, a potential clue towards understanding its physiological function comes from the role of Rho proteins in modulation of the actin cytoskeleton. The inhibition of Rho function with toxin B, or expression of the amino-terminal domain of TC10, disrupts the adipocyte actin cytoskeleton and inhibits GLUT4 translocation. Moreover, the dominant-negative mutant of TC10 disrupts caveolae-associated F-actin structures in adipocytes . The disruption of caveolae with cholesterol-depleting drugs or by overexpression of the inhibitory forms of caveolin-1 completely blocks TC10 activation, as well as the stimulation of glucose transport by insulin . However, direct evidence for an interaction between TC10 and cav-eolin-1 remains vague.
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Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...