MNK1 and MNK2 regulation in HER2-overexpressing breast cancer lines.
MAPK-interacting protein kinases 1 and 2 (MNK1 and MNK2) function downstream of p38 and ERK MAPK, but there are large gaps in our knowledge of how MNKs are regulated and function. As proteins activated in the HER2/Ras/Raf/ERK pathway, the MNKs are of potential interest in HER2-overexpressing cancers. We utilized a panel of breast cell lines (HCC1419, AU565, SKBR3, MCF7, and MCF10A), three of which overexpress HER2, to characterize the amounts and activation status of MNKs and other pathway enzymes (ERKs and RSKs) in these cells. We generated a phosphospecific antibody to Thr(P)-214 in the T-loop of MNKs and found that phosphorylations of both Thr-209 and Thr-214 in human MNK1 are required for activation. Increased phosphorylation and activity of the MNKs correlate with HER2 overexpression, and inhibition of the MNKs reduces colony formation in soft agar. Our work identifies the MNKs as potential therapeutic targets for breast cancer treatments.
Chrestensen
Carol A
CA
Department of Pharmacology, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908.
Shuman
Jacquelyn K
JK
Department of Pharmacology, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908.
Eschenroeder
Andrew
A
Department of Pharmacology, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908.
Worthington
Mark
M
Digestive Health Center of Excellence, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908, and.
Gram
Hermann
H
Arthritis and Bone Metabolism, Novartis Pharma AG, CH-4002 Basel, Switzerland.
Sturgill
Thomas W
TW
Department of Pharmacology, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908. Electronic address: Thomas_Sturgill@virginia.edu.
D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D014443:Tyrosine; D048051:p38 Mitogen-Activated Protein Kinases; C491395:MKNK1 protein, human; C486342:MKNK2 protein, human