Steady-State Levels of Phosphorylated Mitogen-Activated Protein Kinase Kinase 1/2 Determined by Mortalin/HSPA9 and Protein Phosphatase 1 Alpha in KRAS and BRAF Tumor Cells. Mol Cell Biol 2017 Sep 15;37(18)
Date
07/05/2017Pubmed ID
28674184Pubmed Central ID
PMC5574043DOI
10.1128/MCB.00061-17Scopus ID
2-s2.0-85028363255 (requires institutional sign-in at Scopus site) 18 CitationsAbstract
Although deregulation of MEK/extracellular signal-regulated kinase (ERK) activity is a key feature in cancer, high-magnitude MEK/ERK activity can paradoxically induce growth inhibition. Therefore, additional mechanisms may exist to modulate MEK/ERK activity in favor of tumor cell proliferation. We previously reported that mortalin/HSPA9 can facilitate proliferation of certain KRAS and BRAF tumor cells by modulating MEK/ERK activity. In this study, we demonstrated that mortalin can regulate MEK/ERK activity via protein phosphatase 1α (PP1α). We found that PP1α inhibition increases steady-state levels of phosphorylated MEK1/2 in various tumor cells expressing B-RafV600E or K-RasG12C/D Intriguingly, coimmunoprecipitation and in vitro binding assays revealed that mortalin facilitates PP1α-mediated MEK1/2 dephosphorylation by promoting PP1α-MEK1/2 interaction in an ATP-sensitive manner. The region spanning Val482 to Glu491 in the substrate-binding cavity and the substrate lid of mortalin were necessary for these physical interactions, which is consistent with conventional heat shock protein 70 (HSP70)-client interaction mechanisms. Nevertheless, mortalin depletion did not affect cellular PP1α levels or its regulatory phosphorylation, suggesting a nonconventional role for mortalin in promoting PP1α-MEK1/2 interaction. Of note, PP1α was upregulated in human melanoma and pancreatic cancer biopsy specimens in correlation with mortalin upregulation. PP1α may therefore have a role in tumorigenesis in concert with mortalin, which affects MEK/ERK activity in tumor cells.
Author List
Wu PK, Hong SK, Park JIAuthor
Jong-In Park PhD Professor in the Biochemistry department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Cell Line, TumorCell Proliferation
Cell Transformation, Neoplastic
Extracellular Signal-Regulated MAP Kinases
HSP70 Heat-Shock Proteins
Humans
MAP Kinase Kinase 1
MAP Kinase Kinase 2
Melanoma
Mitochondrial Proteins
Pancreatic Neoplasms
Phosphorylation
Protein Phosphatase 1
Proto-Oncogene Proteins B-raf
Proto-Oncogene Proteins p21(ras)
RNA Interference
RNA, Small Interfering