RESUMO
While TGFß signals are anti-proliferative in benign and well-differentiated pancreatic cells, TGFß appears to promote the progression of advanced cancers. To better understand dysregulation of the TGFß pathway, we first generated mouse models of neoplastic disease with TGFß receptor deficiencies. These models displayed reduced levels of pERK irrespective of KRAS mutation. Furthermore, exogenous TGFß led to rapid and sustained TGFBR1-dependent ERK phosphorylation in benign pancreatic duct cells. Similar to results that our group has published in colon cancer cells, inhibition of ERK phosphorylation in duct cells mitigated TGFß-induced upregulation of growth suppressive pSMAD2 and p21, prevented downregulation of the pro-growth signal CDK2 and ablated TGFß-induced EMT. These observations suggest that ERK is a key factor in growth suppressive TGFß signals, yet may also contribute to detrimental TGFß signaling such as EMT. In neoplastic PanIN cells, pERK was not necessary for either TGFß-induced pSMAD2 phosphorylation or CDK2 repression, but was required for upregulation of p21 and EMT indicating a partial divergence between TGFß and MEK/ERK in early carcinogenesis. In cancer cells, pERK had no effect on TGFß-induced upregulation of pSMAD2 and p21, suggesting the two pathways have completely diverged with respect to the cell cycle. Furthermore, inhibition of pERK both reduced levels of CDK2 and prevented EMT independent of exogenous TGFß, consistent with most observations identifying pERK as a tumor promoter. Combined, these data suggest that during carcinogenesis pERK initially facilitates and later antagonizes TGFß-mediated cell cycle arrest, yet remains critical for the pathological, EMT-inducing arm of TGFß signaling.