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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

07/05/2017

Pubmed ID

28674184

Pubmed Central ID

PMC5574043

DOI

10.1128/MCB.00061-17

Scopus ID

2-s2.0-85028363255   8 Citations

Abstract

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 JI

Authors

Jong-In Park PhD Professor in the Biochemistry department at Medical College of Wisconsin
Pui Kei Wu PhD Instructor in the Biochemistry department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Cell Line, Tumor
Cell 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
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a