The Effect of Laminin on Interaction between G‐beta and PI3‐Kinase/Akt signaling pathway in Skeletal Muscle

Abstract

Previously (Am. J. Physiol. Cell Physiol. 288: , 2005), we showed that laminin-binding to the dystrophin glycoprotein complex (DGC) of skeletal muscle causes a heterotrimeric G-protein, (Gαβ γ) to bind changing the activation state of the Gsα subunit . Others (Langenbach and Rando, Muscle and Nerve 26: , 2002) showed that laminin-binding to this complex also leads to Akt activation. Since Gβ γ, released when Gsα is activated, is known to bind to phosphatidylinositol 3-kinase (PI3K) which activates Akt, we investigated whether Akt activation results from Gβ γ-binding. Laminin-Sepharose binds the DGC and not β1-integrins under the conditions used. Laminin-Sepharose binds a complex containing PI3K in the presence of non-hydrolysable GTPγS but not in the presence of GDP. This indicates that PI3K is only bound under conditions when Gβ γ is dissociated from Gsα. Gβ γ is associated with PI3K and with Akt under these conditions. Using microsomes containing endogenous laminin, Gβ γ is associated with both PI3K and Akt and Akt is activated. Laminin depletion results in less binding and activation and when exogenous laminin is added, binding and activation is restored. These results shown that DGC-Gβ γ is binding PI3K and Akt in a laminin-dependent manner and activating pAkt. Collectively, the results show that DGC-bound Gβ γ activates PI3K/Akt signaling in a laminin-dependent manner. (Supported by NIH AR051440 and The Muscular Dystrophy Association grant #3789)