title: Dynamic distribution of ERK, p38 and JNK during the development of pancreatic ductal adenocarcinoma.
abstract: We recently discovered that oncogenic c-kit is highly expressed concomitantly with the development of pancreatic ductal adenocarcinoma (PDAC). Since oncogenic c-kit may activate major pathways of protein tyrosine phosphorylation, we decided to investigate this issue in the major protein phosphorylation cascades. In normal pancreas labeling with antiphosphorylated ERK1/2 (pERK1/2) antibody was mainly confined to islets of Langerhans in close overlapping with insulin containing cells. Phosphorylated p38 (pp38) showed a similar pattern of distribution, while only weak labeling was evident for pJNK and no labeling of pMEK was observed. As expected, general ERK1/2 (gERK1/2), general p38 (gp38), general JNK (gJNK) as well as general MEK (gMEK) were all evident in islets of Langerhans and in the exocrine tissue. In early development of PDAC, pERK1/2 and pp38 retained their localization in islets of Langerhans. Intensive staining of pERK1/2 was also evident in the cancerous ducts, while the labeling with antibodies to pp38 was more moderate. While pJNK staining in islets of Langerhans was weak, with no labeling in the cancerous ducts, antibodies to gJNK revealed intensive staining suggesting the weak staining of pJNK is not due to the lack of the enzyme. In a more advanced stage of PDAC the carcinomas were clearly stained with pERK1/2 and pp38, while moderate staining with pJNK was also evident. In liver metastases, the cancer cells were heavily labeled with all three phospho-MAPKs. It should be noted that the localization of all three kinases was mainly in the cell nuclei. In the more advanced stage of PDAC, heavy labeling was evident using antibodies to gERK1/2, gp38, gJNK and gMEK. However, no labeling to pMEK was evident in parallel sections. Our data suggest that both in normal and cancerous pancreas, most of the MAPK activities are located in islets of Langerhans and cancerous ducts. It is suggested that using inhibitors to protein kinases may attenuate the progression of the disease.
authors.affiliation: Department of Molecular Cell Biology, The Weizmann Institute of Science, 234 Herzl Street, Rehovot 76100, Israel. Electronic address: Abraham.amsterdam@weizmann.ac.il.
authors.forename: Abraham
authors.initials: A
authors.lastname: Amsterdam
authors.affiliation: Department of Molecular Cell Biology, The Weizmann Institute of Science, 234 Herzl Street, Rehovot 76100, Israel.
authors.forename: Lotem
authors.initials: L
authors.lastname: Shpigner
authors.affiliation: Department of Veterinary Resources, The Weizmann Institute of Science, 234 Herzl Street, Rehovot 76100, Israel.
authors.forename: Calanit
authors.initials: C
authors.lastname: Raanan
authors.affiliation: Wolfson Hospital, Holon 58100, Israel.
authors.forename: Letizia
authors.initials: L
authors.lastname: Schreiber
authors.affiliation: Department of Gastroentrology, Kaplan Medical Center, Rehovot 76100, Israel.
authors.forename: Ehud
authors.initials: E
authors.lastname: Melzer
authors.affiliation: Department of Biological Regulation, The Weizmann Institute of Science, 234 Herzl Street, Rehovot 76100, Israel.
authors.forename: Rony
authors.initials: R
authors.lastname: Seger
mesh_terms: D000368:Aged; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D048049:Extracellular Signal-Regulated MAP Kinases; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4
keywords: ERK1/2; Islets of Langerhans; JNK; PDAC; p38; β cells