Unc119 regulates myofibroblast differentiation through the activation of Fyn and the p38 MAPK pathway.
Unc119 is an adaptor protein that is involved in the development of the vertebrate nervous system. We have shown that Unc119 stimulates the induction of alpha-smooth muscle actin (alpha-SMA) and myofibroblast differentiation by TGF-beta in human lung fibroblasts. Unc119 increases the kinase activity of Fyn and associates with it in coprecipitation and colocalization studies. Phosphorylation and activation of Fyn in response to TGF-beta and platelet-derived growth factor is delayed in Unc119-deficient cells. This delay translates into suppressed cell proliferation. In Src family kinase-deficient (SYF) cells, Unc119 knockdown does not affect cell proliferation. The result suggests that Unc119 interacts with Fyn in the early stages of signal generation and its presence is essential for conducive signal transduction. Unc119 overexpression does not stimulate alpha-SMA in SYF cells and this defect is restored upon reconstitution with Fyn indicating that Unc119 stimulation of alpha-SMA requires at least Fyn. Unc119 overexpression stimulated p38, but not JNK, phosphorylation. Blocking p38 MAPK resulted in reduced alpha-SMA expression by Unc119 suggesting that the p38 pathway regulates Unc119-induced myofibroblast differentiation. Unc119 stimulates the production of TGF-beta and IL-6, known inducers of myofibroblast differentiation. Thus, Unc119 regulates receptor-mediated signal transduction and myofibroblast differentiation by activating Fyn and the p38 MAPK pathway. Using primary lung fibroblasts from patients with fibrotic lung diseases and control subjects, we show that the expression of alpha-smooth muscle actin is highly correlated with that of Unc119. Taken together, our results suggest that Unc119 plays an important role in fibrotic processes through myofibroblast differentiation.
Vepachedu
Ramarao
R
National Jewish Medical and Research Center and University of Colorado Health Sciences Center, Denver, CO 80206, USA.
Gorska
Magdalena M
MM
Singhania
Neil
N
Cosgrove
Gregory P
GP
Brown
Kevin K
KK
Alam
Rafeul
R
D000199:Actins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000235:genetics / Q000502:physiology; D005136:Eye Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D005347:Fibroblasts / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D008868:Microtubule Proteins / Q000502:physiology*; D041681:NIH 3T3 Cells; D051076:Proto-Oncogene Proteins c-fyn / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D011658:Pulmonary Fibrosis / Q000201:enzymology / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000502:physiology; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*; D019061:src-Family Kinases / Q000235:genetics / Q000502:physiology
D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D005136:Eye Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008868:Microtubule Proteins; D016212:Transforming Growth Factor beta; C098032:UNC119 protein, human; C489115:Unc119 protein, mouse; C494957:FYN protein, human; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn; D019061:src-Family Kinases; D048051:p38 Mitogen-Activated Protein Kinases