Cdo promotes neuronal differentiationviaactivation of the p38 mitogen‐activated protein kinase pathway

Abstract

Neural basic helix-loop-helix transcription factors (bHLHs) control many aspects of neurogenesis, such as proliferation, fate determination, and differentiation. We have previously shown that the promyogenic cell surface receptor Cdo modulates the Cdc42 and p38 mitogen-activated protein kinase (MAPK) pathways via a direct association with two scaffold-type proteins, JLP and Bnip-2, to regulate activities of myogenic bHLH factors and myogenic differentiation. We report here that Cdo uses similar regulatory mechanisms to promote neuronal differentiation. Expression of JLP, a scaffold protein for p38MAPK, and Bnip-2, a regulator of Cdc42, is increased during differentiation of C17.2 neural precursor cells and P19 embryonal carcinoma cells. These molecules regulate Cdc42 and p38MAPK activities, which increase in a Cdo-dependent manner during neuronal differentiation of C17.2 cells and retinoic acid-treated P19 cells. Furthermore, enhancement or reduction of Cdc42 and p38MAPK activities enhances or reduces, respectively, neuronal differentiation of these cell lines. Cdc42 and p38MAPK activities also promote heterodimerization of neurogenin1 and E47, suggesting that one way they promote neurogenesis is via regulation of neural bHLH factor activities. These results imply that a conserved intracellular signaling mechanism initiated by Cdo regulates the activities of tissue-specific bHLH factors and therefore functions as a key regulator of differentiation of several different cell lineages.

N-cadherin ligation, but not Sonic hedgehog binding, initiates Cdo-dependent p38α/β MAPK signaling in skeletal myoblasts

“…3B). Taking the results together, Ncad ligation induced pp38 in a short-term signaling assay in a manner very similar to the activation of pp38 seen in differentiating myoblasts (i.e., each is sensitive to disruption of Ncad-Cdo interaction, depletion of Cdo and its intracellular binding proteins JLP and Bnip-2, and reduction of Cdc42 activity) (6,7,10).…”

“…Bnip-2 and JLP do not interact directly but associate through their mutual ability to bind Cdo, implying that Cdc42 bound to Cdo via Bnip-2 signals to activate p38 bound to Cdo via JLP (6). Cdo/Bnip-2/JLP/p38 signaling also promotes neuronal differentiation (10). In contrast, Cdo and Bnip-2 are dispensable for TNFα-and hyperosmotic stress-induced p38 activity, indicating that modes of p38 activation in cell differentiation and stress responses are distinct (6).…”

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

“…Bnip-2 and JLP associate indirectly in a Cdo-dependent manner, implying that Cdc42 bound to Cdo via Bnip-2 signals to activate p38 bound to Cdo via JLP (20). A similar pathway regulates neuronal differentiation in vitro (34), and we have proposed that formation of this signaling complex represents one mechanism for differentiationspecific activation of p38 MAPK. It is therefore of obvious interest to identify additional components and regulators of Cdocontaining signaling complexes involved in cell differentiation.…”

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

“…In agreement with this notion, Cdo Ϫ/Ϫ primary myoblasts are unable to induce the differentiation-specific p38MAPK, and their defective differentiation is rescued by the expression of an activated form of MKK6, an immediate upstream kinase of p38MAPK. In addition, Cdo-mediated p38MAPK activation is required for the neuronal differentiation of C17.2 neuronal progenitor cells and P19 embryonal carcinoma cells (37). It is anticipated that p38MAPK activation by the Cdo-JLP complex will require specific MAP3Ks.…”