title: TGFβ engages MEK/ERK to differentially regulate benign and malignant pancreas cell function.
abstract: While TGFβ signals are anti-proliferative in benign and well-differentiated pancreatic cells, TGFβ appears to promote the progression of advanced cancers. To better understand dysregulation of the TGFβ pathway, we first generated mouse models of neoplastic disease with TGFβ receptor deficiencies. These models displayed reduced levels of pERK irrespective of KRAS mutation. Furthermore, exogenous TGFβ 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 TGFβ-induced upregulation of growth suppressive pSMAD2 and p21, prevented downregulation of the pro-growth signal CDK2 and ablated TGFβ-induced EMT. These observations suggest that ERK is a key factor in growth suppressive TGFβ signals, yet may also contribute to detrimental TGFβ signaling such as EMT. In neoplastic PanIN cells, pERK was not necessary for either TGFβ-induced pSMAD2 phosphorylation or CDK2 repression, but was required for upregulation of p21 and EMT indicating a partial divergence between TGFβ and MEK/ERK in early carcinogenesis. In cancer cells, pERK had no effect on TGFβ-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 TGFβ, consistent with most observations identifying pERK as a tumor promoter. Combined, these data suggest that during carcinogenesis pERK initially facilitates and later antagonizes TGFβ-mediated cell cycle arrest, yet remains critical for the pathological, EMT-inducing arm of TGFβ signaling.
authors.affiliation: University of Illinois College of Medicine, Chicago, IL, USA.
authors.forename: D R
authors.initials: DR
authors.lastname: Principe
authors.affiliation: Department of Medicine, University of Illinois, Chicago, IL, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Diaz
authors.affiliation: Department of Medicine, University of Illinois, Chicago, IL, USA.
authors.forename: C
authors.initials: C
authors.lastname: Torres
authors.affiliation: Department of Medicine, University of Illinois, Chicago, IL, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Mangan
authors.affiliation: Department of Medicine, University of Illinois, Chicago, IL, USA.
authors.forename: B
authors.initials: B
authors.lastname: DeCant
authors.affiliation: Department of Medicine, University of Illinois, Chicago, IL, USA.
authors.forename: R
authors.initials: R
authors.lastname: McKinney
authors.affiliation: Ontario Cancer Institute/Princess Margaret Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: M-S
authors.initials: MS
authors.lastname: Tsao
authors.affiliation: Department of Surgery, University of California San Diego, San Diego, CA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Lowy
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: H G
authors.initials: HG
authors.lastname: Munshi
authors.affiliation: Department of Medicine, University of Illinois, Chicago, IL, USA.
authors.forename: B
authors.initials: B
authors.lastname: Jung
authors.affiliation: Department of Medicine, University of Illinois, Chicago, IL, USA.
authors.forename: P J
authors.initials: PJ
authors.lastname: Grippo
mesh_terms: D000818:Animals; D015153:Blotting, Western; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D016212:Transforming Growth Factor beta; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases