Mixed lineage kinase 3 promotes breast tumorigenesis via phosphorylation and activation of p21-activated kinase 1.
Animals
Breast Neoplasms
/ metabolism
Cell Line, Tumor
Cell Movement
Enzyme Activation
Female
Humans
MAP Kinase Kinase Kinases
/ genetics
Mice, SCID
Phosphorylation
Serine
/ metabolism
Xenograft Model Antitumor Assays
p21-Activated Kinases
/ chemistry
Mitogen-Activated Protein Kinase Kinase Kinase 11
Journal
Oncogene
ISSN: 1476-5594
Titre abrégé: Oncogene
Pays: England
ID NLM: 8711562
Informations de publication
Date de publication:
05 2019
05 2019
Historique:
received:
17
08
2018
accepted:
07
12
2018
revised:
28
11
2018
pubmed:
22
1
2019
medline:
24
10
2019
entrez:
22
1
2019
Statut:
ppublish
Résumé
Mixed lineage kinase 3 (MLK3), a MAP3K member has been envisioned as a viable drug target in cancer, yet its detailed function and signaling is not fully elucidated. We identified that MLK3 tightly associates with an oncogene, PAK1. Mammalian PAK1 being a Ste20 (MAP4K) member, we tested whether it is an upstream regulator of MLK3. In contrast to our hypothesis, MLK3 activated PAK1 kinase activity directly, as well as in the cells. Although, MLK3 can phosphorylate PAK1 on Ser133 and Ser204 sites, PAK1S133A mutant is constitutively active, whereas, PAK1S204A is not activated by MLK3. Stable overexpression of PAK1S204A in breast cancer cells, impedes migration, invasion, and NFĸB activity. In vivo breast cancer cell tumorigenesis is significantly reduced in tumors expressing PAK1S204A mutant. These results suggest that mammalian PAK1 does not act as a MAP4K and MLK3-induced direct activation of PAK1 plays a key role in breast cancer tumorigenesis.
Identifiants
pubmed: 30664689
doi: 10.1038/s41388-019-0690-0
pii: 10.1038/s41388-019-0690-0
pmc: PMC7568686
mid: NIHMS1635508
doi:
Substances chimiques
Serine
452VLY9402
PAK1 protein, human
EC 2.7.11.1
p21-Activated Kinases
EC 2.7.11.1
MAP Kinase Kinase Kinases
EC 2.7.11.25
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
3569-3584Subventions
Organisme : BLRD VA
ID : IK6 BX004855
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA178063
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA216410
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA188427
Pays : United States
Organisme : BLRD VA
ID : I01 BX003296
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA176846
Pays : United States
Organisme : NIH HHS
ID : S10 OD018445
Pays : United States
Organisme : BLRD VA
ID : I01 BX002703
Pays : United States
Commentaires et corrections
Type : ErratumIn
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