PMID- 35064619
OWN - NLM
STAT- MEDLINE
DCOM- 20220706
LR  - 20220721
IS  - 1878-0261 (Electronic)
IS  - 1574-7891 (Print)
IS  - 1574-7891 (Linking)
VI  - 16
IP  - 13
DP  - 2022 Jul
TI  - TLK1-mediated MK5-S354 phosphorylation drives prostate cancer cell motility and 
      may signify distinct pathologies.
PG  - 2537-2557
LID - 10.1002/1878-0261.13183 [doi]
AB  - Metastases account for the majority of prostate cancer (PCa) deaths, and 
      targeting them is a major goal of systemic therapy. We identified a novel 
      interaction between two kinases: tousled-like kinase 1 (TLK1) and MAP 
      kinase-activated protein kinase 5 (MK5) that promotes PCa spread. In PCa 
      progression, TLK1-MK5 signalling appears to increase following antiandrogen 
      treatment and in metastatic castration-resistant prostate cancer (mCRPC) 
      patients. Determinations of motility rates (2D and 3D) of different TLK1- and 
      MK5-perturbed cells, including knockout (KO) and knockdown (KD), as well as the 
      use of specific inhibitors, showed the importance of these two proteins for 
      in vitro dissemination. We established that TLK1 phosphorylates MK5 on three 
      residues (S160, S354 and S386), resulting in MK5 activation, and additionally, 
      mobility shifts of MK5 also supported its phosphorylation by TLK1 in transfected 
      HEK 293 cells. Expression of MK5-S354A or kinase-dead MK5 in MK5-depleted mouse 
      embryonic fibroblast (MEF) cells failed to restore their motility compared with 
      that of wild-type (WT) MK5-rescued MK5(-/-) MEF cells. A pMK5-S354 antiserum was 
      used to establish this site as an authentic TLK1 target in androgen-sensitive 
      human prostate adenocarcinoma (LNCaP) cells, and was used in immunohistochemistry 
      (IHC) studies of age-related PCa sections from TRAMP (transgenic adenocarcinoma 
      of the mouse prostate) mice and to probe a human tissue microarray (TMA), which 
      revealed pMK5-S354 level is correlated with disease progression (Gleason score 
      and nodal metastases). In addition, The Cancer Genome Atlas (TCGA) analyses of 
      PCa expression and genome-wide association study (GWAS) relations identify TLK1 
      and MK5 as potential drivers of advanced PCa and as markers of mCRPC. Our work 
      suggests that TLK1-MK5 signalling is functionally involved in driving PCa cell 
      motility and clinical features of aggressiveness; hence, disruption of this axis 
      may inhibit the metastatic spread of PCa.
CI  - (c) 2022 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on 
      behalf of Federation of European Biochemical Societies.
FAU - Khalil, Md Imtiaz
AU  - Khalil MI
AD  - Department of Biochemistry and Molecular Biology, LSU Health Sciences Center, 
      Shreveport, LA, USA.
FAU - Singh, Vibha
AU  - Singh V
AD  - Department of Biochemistry and Molecular Biology, LSU Health Sciences Center, 
      Shreveport, LA, USA.
FAU - King, Judy
AU  - King J
AD  - Department of Pathology and Translational Pathobiology, LSU Health Sciences 
      Center, Shreveport, LA, USA.
FAU - De Benedetti, Arrigo
AU  - De Benedetti A
AUID- ORCID: 0000-0002-4198-8647
AD  - Department of Biochemistry and Molecular Biology, LSU Health Sciences Center, 
      Shreveport, LA, USA.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20220203
PL  - United States
TA  - Mol Oncol
JT  - Molecular oncology
JID - 101308230
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 6YHG2VE3IX (MAP-kinase-activated kinase 5)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (TLK1 protein, human)
SB  - IM
MH  - *Adenocarcinoma/pathology
MH  - Animals
MH  - Cell Movement
MH  - Fibroblasts/metabolism
MH  - Genome-Wide Association Study
MH  - HEK293 Cells
MH  - Humans
MH  - *Intracellular Signaling Peptides and Proteins/metabolism
MH  - Male
MH  - Mice
MH  - Phosphorylation
MH  - *Prostatic Neoplasms, Castration-Resistant/pathology
MH  - *Protein Serine-Threonine Kinases/metabolism
PMC - PMC9251878
OTO - NOTNLM
OT  - MK5/MAPKAPK5/PRAK
OT  - PCa TMA
OT  - TLK1/1B
OT  - cell motility
OT  - prostate cancer metastasis
COIS- The authors declare that no conflict of interest exist.
EDAT- 2022/01/23 06:00
MHDA- 2022/07/07 06:00
PMCR- 2022/07/01
CRDT- 2022/01/22 05:47
PHST- 2021/12/06 00:00 [revised]
PHST- 2021/10/15 00:00 [received]
PHST- 2022/01/19 00:00 [accepted]
PHST- 2022/01/23 06:00 [pubmed]
PHST- 2022/07/07 06:00 [medline]
PHST- 2022/01/22 05:47 [entrez]
PHST- 2022/07/01 00:00 [pmc-release]
AID - MOL213183 [pii]
AID - 10.1002/1878-0261.13183 [doi]
PST - ppublish
SO  - Mol Oncol. 2022 Jul;16(13):2537-2557. doi: 10.1002/1878-0261.13183. Epub 2022 Feb 
      3.