Laminin-α1 LG4-5 domain binding to dystroglycan mediates muscle cell survival, growth, and the AP-1 and NF-κB transcription factors but also has adverse effects

Zhou YW, Munoz J, Jiang D, Jarrett HW. Laminin-alpha(1) LG4-5 domain binding to dystroglycan mediates muscle cell survival, growth, and the AP-1 and NF-kappa B transcription factors but also has adverse effects. Am J Physiol Cell Physiol 302: C902-C914, 2012. First published December 7, 2011; doi: 10.1152/ajpcell.00118.2011.-In our previous studies, we showed laminin binds alpha-dystroglycan in the dystrophin glycoprotein complex and initiates cell signaling pathways. Here, differentiated C2C12 myocytes serve as a model of skeletal muscle. C2C12 cells have a biphasic response to the laminin-alpha(1) laminin globular (LG) 4-5 domains (1E3) dependent on the concentration used; at low concentrations of 1E3 (<1 mu g/ml), myoblast proliferation is increased while higher concentrations (<1 mu g/ml) cause apoptosis in myoblasts and differentiated myotubes. This alters the activation of the transcription factors activator protein-1 (AP-1) and NF-kappa B via laminin-dystrophin glycoprotein complex (DGC)-src-grb2-sos1-Rac1-Pak1-c-jun N-terminal kinase (JNK)p46 and laminin-DGC-G beta gamma-phosphatidylinositol 3-kinase (PI3K)-Akt pathways, respectively. A specific antibody against Ser(63) phosphorylated c-jun completely blocks or supershifts the AP-1-DNA binding resulting from laminin binding but only partially blocks or supershifts the AP-1-DNA binding resulting from 1E3. This suggests that AP-1 contains phosphorylated c-jun in the presence of hololaminin but contains a different composition in the presence of 1E3. Nuclear NF-kappa B was only upregulated by a low concentration of 1E3 and is then diminished by a higher concentration; it also has a biphasic response. Nuclear localization of NF-kappa B is affected by PI3K/Akt signaling, and DGC associated PI3K activity also shows a biphasic response to 1E3. Furthermore, our data suggest that activation of c-jun N-terminal kinase participates in the cell survival pathway and suggest that NF-kappa B is involved in both survival and cell death. A model is presented which incorporates these observations.