Cdo Binds Abl To Promote p38α/β Mitogen-Activated Protein Kinase Activity and Myogenic Differentiation

Abstract

The p38 mitogen-activated protein kinase (MAPK) pathway is required for differentiation of skeletal myoblasts, but how the pathway is activated during this process is not well understood. One mechanism involves the cell surface receptor Cdo (also known as Cdon), which binds to Bnip-2 and JLP, scaffold proteins for Cdc42 and p38, respectively; formation of these complexes results in Bnip-2/Cdc42-dependent activation of p38. It has been reported that the tyrosine kinase Abl promotes myogenic differentiation in a manner dependent on its cytoplasmic localization, but the cytoplasmic signaling proteins with which it interacts to achieve this effect are unidentified. We report that Abl associates with both Cdo and JLP during myoblast differentiation. Abl binds a proline-rich motif in Cdo via its SH3 domain, and these regions of Abl and Cdo are required for their promyogenic effects. Cdo is important for full Abl kinase activity, and Abl is necessary for full activation of p38 MAPK, during myogenic differentiation. As seen with myoblasts depleted of Cdo, the diminished differentiation displayed by Abl-depleted cells is rescued by the expression of an activated form of the immediate upstream p38-activating kinase MAPK kinase 6. Abl's promyogenic effect is therefore linked to a multiprotein cell surface complex that regulates differentiation-dependent p38 activation.

Essential Role for p38α MAPK But Not p38γ MAPK in Igf2 Expression and Myoblast Differentiation

“…Even though extracellular activation of PI3K/Akt by receptor tyrosine kinases (such as the IGF-IR) is well established, the stimuli that activate p38 MAPK have been more elusive. The importance of cell-cell contact in the activation of p38 has recently been identified (18,19). We have further demonstrated that cross communication between PI3K/Akt and p38 MAPK is necessary for efficient myoblast differentiation (11), thus integrating extracellular signals.…”

TGF-β-activated Kinase 1 (TAK1) and Apoptosis Signal-regulating Kinase 1 (ASK1) Interact with the Promyogenic Receptor Cdo to Promote Myogenic Differentiation via Activation of p38MAPK Pathway

“…6K). In our recent report (43), the non-receptor tyrosine kinase Abl interacts with the cytoplasmic region of Cdo and JLP and cooperates with JLP and Cdo to activate p38MAPK and promote myoblast differentiation. It is possible that Abl may be responsible for activating ASK1 and TAK1 to initiate the downstream signaling pathway.…”

“…It is possible that Abl may be responsible for activating ASK1 and TAK1 to initiate the downstream signaling pathway. However Abl may not act solely as a kinase in this context, as a kinasedeficient mutant form of Abl retains partial activity in stimulating p38MAPK activity (43). Based on these data, we propose that N-cadherin-mediated cell contact may induce a complex formation of Cdo with JLP, ASK1/TAK1, and p38MAPK, thereby enhancing the activation of p38MAPK.…”

“…BrdU Incorporation Assay-C2C12 cells stably expressing ASK1, TAK1, shAsk1-1, shAsk1-2, shTak1-1, or shTak1-2 were incubated with BrdU for 10 min in growth medium and analyzed as described previously (43). Briefly, cells were rinsed with PBS twice and then fixed for 10 min at room temperature with 4% paraformaldehyde.…”

Epicatechin elicits MyoD-dependent myoblast differentiation and myogenic conversion of fibroblasts

“…Myoblast C2C12 cells, embryonic fibroblast 10T1/2 cells and embryonic kidney 293T cells were cultured as described previously [14, 15]. To induce differentiation of C2C12 myoblasts, cells at near confluence were switched from DMEM containing 15% FBS (fetal bovine serum; growth medium, GM) to DMEM containing 2% HS (horse serum; differentiation medium, DM) and myotube formation was observed normally at approximately 2–3 days of differentiation.…”