Convergence of Igf2 expression and adhesion signalling via RhoA and p38 MAPK enhances myogenic differentiation.
Cell-cell contact is essential for appropriate co-ordination of development and it initiates significant signalling events. During myogenesis, committed myoblasts migrate to sites of muscle formation, align and form adhesive contacts that instigate cell-cycle exit and terminal differentiation into multinucleated myotubes; thus myogenesis is an excellent paradigm for the investigation of signals derived from cell-cell contact. PI3-K and p38 MAPK are both essential for successful myogenesis. Pro-myogenic growth factors such as IGF-II activate PI3-K via receptor tyrosine kinases but the extracellular cues and upstream intermediates required for activation of the p38 MAPK pathway in myoblast differentiation are not known. Initial observations suggested a correlation between p38 MAPK phosphorylation and cell density, which was also related to N-cadherin levels and Igf2 expression. Subsequent studies using N-cadherin ligand, dominant-negative N-cadherin, constitutively active and dominant-negative forms of RhoA, and MKK6 and p38 constructs, reveal a novel pathway in differentiating myoblasts that links cell-cell adhesion via N-cadherin to Igf2 expression (assessed using northern and promoter-reporter analyses) via RhoA and p38alpha and/or beta but not gamma. We thus define a regulatory mechanism for p38 activation that relates cell-cell-derived adhesion signalling to the synthesis of the major fetal growth factor, IGF-II.
Lovett
Fiona A
FA
The Babraham Institute, Babraham Research Campus, Cambridge, CB2 4AT, UK.
Gonzalez
Ivelisse
I
Salih
Dervis A M
DA
Cobb
Laura J
LJ
Tripathi
Gyanendra
G
Cosgrove
Ruth A
RA
Murrell
Adele
A
Kilshaw
Peter J
PJ
Pell
Jennifer M
JM
D000818:Animals; D015820:Cadherins / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology*; D002452:Cell Count; D002454:Cell Differentiation; D002478:Cells, Cultured; D007335:Insulin-Like Growth Factor II / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism; D051379:Mice; D024510:Muscle Development; D050505:Mutant Proteins / Q000378:metabolism; D032446:Myoblasts / Q000166:cytology* / Q000378:metabolism; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
D015820:Cadherins; C489083:Cdh2 protein, mouse; D007527:Isoenzymes; D050505:Mutant Proteins; D007335:Insulin-Like Growth Factor II; D048051:p38 Mitogen-Activated Protein Kinases; D020742:rhoA GTP-Binding Protein