title: Phosphorylation of Mps1 by BRAFV600E prevents Mps1 degradation and contributes to chromosome instability in melanoma.
abstract: Activating BRAF mutations that deregulate the mitogen-activated protein kinase (MAPK) pathway commonly occur in cancer. BRAF(V600E) induces centrosome amplification and spindle abnormalities that result in aneuploidy. We find modification of Mps1 is critical for contributing to centrosome amplification and chromosome instability induced by BRAF(V600E). Phosphorylation of Mps1 at residue S281 induced by BRAF(V600E) stabilizes Mps1 protein by preventing its ubiquitination by APC/C and subsequent degradation, allowing the non-degraded protein to accumulate at centrosomes. Cells in which endogenous Mps1 was replaced with a phospho-mimetic Mps1 mutant are viable but amplify centrosomes and missegregate chromosomes frequently. Importantly, analysis of tumor micro arrays revealed that phospho-MAPK and S281-phosphorylated Mps1 were highly correlated in human melanoma tissues, implying that MAPK contributes to defects in the degradation of Mps1 in situ. We propose that continuously activated BRAF(V600E) signaling may be a possible mechanism for the deregulation of Mps1 stability and kinase activity in human tumors, and that persistent phosphorylation of Mps1 through BRAF(V600E) signaling is a key event in disrupting the control of centrosome duplication and chromosome stability that may contribute to tumorigenesis. Our findings raise the possibility that targeting the oncogenic BRAF and S281-phosphorylated Mps1, especially when used in combination could potentially provide great therapeutic opportunities for cancer treatment.
authors.affiliation: Department of General Surgery, The First Hospital, Shanxi Medical University, Taiyuan, People's Republic of China.
authors.forename: J
authors.initials: J
authors.lastname: Liu
authors.forename: X
authors.initials: X
authors.lastname: Cheng
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: S
authors.initials: S
authors.lastname: Li
authors.forename: H
authors.initials: H
authors.lastname: Cui
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.forename: R
authors.initials: R
authors.lastname: Shi
authors.forename: Z
authors.initials: Z
authors.lastname: Zhao
authors.forename: C
authors.initials: C
authors.lastname: He
authors.forename: C
authors.initials: C
authors.lastname: Wang
authors.forename: H
authors.initials: H
authors.lastname: Zhao
authors.forename: C
authors.initials: C
authors.lastname: Zhang
authors.forename: H A
authors.initials: HA
authors.lastname: Fisk
authors.forename: T M
authors.initials: TM
authors.lastname: Guadagno
authors.forename: Y
authors.initials: Y
authors.lastname: Cui
mesh_terms: D000782:Aneuploidy; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D018385:Centrosome / Q000378:metabolism; D043171:Chromosomal Instability; D006801:Humans; D008545:Melanoma / Q000235:genetics*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D054875:Ubiquitination
chemical_list: D018797:Cell Cycle Proteins; D011505:Protein-Tyrosine Kinases; C482119:BRAF protein, human; D017346:Protein Serine-Threonine Kinases; D048493:Proto-Oncogene Proteins B-raf; C075840:TTK protein, human