Insulin Stimulates the Activation of the Casitas b‐lymphoma (Cbl) Protein in Striated Skeletal Muscle

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Insulin activates glucose transport in adipose and striated muscle cells by stimulating the recruitment of intracellular vesicles containing the glucose transporter GLUT4 to the plasma membrane. In adipocytes two insulin signaling cascades have been implicated in this process: the insulin receptor substrate/phosphatidyl inositol 3 kinase-dependent pathway and the proto-oncogene Casitas b- lymphoma (c-Cbl) dependent pathway. The objective of our study was to examine whether the Cbl-dependent pathway is activated by insulin in striated muscle cells. The components of the Cbl pathway were expressed in both cultured L6 myotubes and in muscle tissue in vivo. Insulin induced the phosphosphorylation of Cbl in the tyrosine residues and the recruitment of the protein to the lipid raft microdomains of the plasma membrane in L6 cells. Palmitate-induced insulin resistance inhibited the phosphorylation of Cbl but not Cbl expression in L6 cells. In vivo, insulin administration induced the phosphorylation of Cbl in adipose, heart, and soleus muscle, but no phosphorylation was observed in hindlimb muscle. In agreement with this, activation of the downstream GTP binding protein TC10 was observed in heart and adipose tissue, following 5 minutes of insulin treatment. TC10 was not activated in hindlimb muscle. Streptozotocin-induced insulin deficiency severely downregulated Cbl and CAP expression in heart and moderate reductions in Cbl protein levels were also observed in adipose tissue and soleus muscle. Overall our findings suggest that insulin induces the activation of Cbl in muscle cells and that this signaling pathway is inhibited in insulin-resistant and insulin-deficient states. The regulation of this pathway in cardiac cells may be important for the regulation of glucose uptake in this tissue during normal and pathological conditions. Funding: DAREF and ADA.