Akt-mediated Ephexin1-Ras interaction promotes oncogenic Ras signaling and colorectal and lung cancer cell proliferation.
Amino Acid Sequence
Animals
Cell Line, Tumor
Cell Proliferation
Colorectal Neoplasms
/ metabolism
Gene Expression Regulation, Neoplastic
Guanine Nucleotide Exchange Factors
/ chemistry
HEK293 Cells
Humans
Lung Neoplasms
/ metabolism
MAP Kinase Signaling System
Male
Mice, Inbred BALB C
Mice, Nude
Models, Biological
Oncogenes
Phosphorylation
Phosphoserine
/ metabolism
Prognosis
Protein Binding
Protein Domains
Proto-Oncogene Proteins c-akt
/ metabolism
RNA, Messenger
/ genetics
Up-Regulation
ras Proteins
/ metabolism
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
28 10 2021
28 10 2021
Historique:
received:
20
08
2021
accepted:
13
10
2021
revised:
12
10
2021
entrez:
29
10
2021
pubmed:
30
10
2021
medline:
3
2
2022
Statut:
epublish
Résumé
Ephexin1 was reported to be highly upregulated by oncogenic Ras, but the functional consequences of this remain poorly understood. Here, we show that Ephexin1 is highly expressed in colorectal cancer (CRC) and lung cancer (LC) patient tissues. Knockdown of Ephexin1 markedly inhibited the cell growth of CRC and LC cells with oncogenic Ras mutations. Ephexin1 contributes to the positive regulation of Ras-mediated downstream target genes and promotes Ras-induced skin tumorigenesis. Mechanically, Akt phosphorylates Ephexin1 at Ser16 and Ser18 (pSer16/18) and pSer16/18 Ephexin1 then interacts with oncogenic K-Ras to promote downstream MAPK signaling, facilitating tumorigenesis. Furthermore, pSer16/18 Ephexin1 is associated with both an increased tumor grade and metastatic cases of CRC and LC, and those that highly express pSer16/18 exhibit poor overall survival rates. These data indicate that Ephexin1 plays a critical role in the Ras-mediated CRC and LC and pSer16/18 Ephexin1 might be an effective therapeutic target for CRC and LC.
Identifiants
pubmed: 34711817
doi: 10.1038/s41419-021-04332-0
pii: 10.1038/s41419-021-04332-0
pmc: PMC8553951
doi:
Substances chimiques
Guanine Nucleotide Exchange Factors
0
NGEF protein, human
0
RNA, Messenger
0
Phosphoserine
17885-08-4
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
ras Proteins
EC 3.6.5.2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1013Subventions
Organisme : National Research Foundation of Korea (NRF)
ID : 2019R1A6A3A01092483
Organisme : National Research Foundation of Korea (NRF)
ID : 2015R1A5A2009070
Organisme : National Research Foundation of Korea (NRF)
ID : 2021R1A2C2005652
Informations de copyright
© 2021. The Author(s).
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