PMID- 31723029
OWN - NLM
STAT- MEDLINE
DCOM- 20200622
LR  - 20231213
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 294
IP  - 52
DP  - 2019 Dec 27
TI  - Dual-specificity tyrosine phosphorylation-regulated kinase 1A ameliorates insulin 
      resistance in neurons by up-regulating IRS-1 expression.
PG  - 20164-20176
LID - 10.1074/jbc.RA119.010809 [doi]
AB  - Insulin resistance in the brain is a pathological mechanism that is shared 
      between Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM). Although 
      aberrant expression and phosphorylation of insulin receptor substrate 1 (IRS-1) 
      contribute to insulin resistance, the underlying mechanism remains elusive. In 
      this study, we used several approaches, including adeno-associated virus-based 
      protein overexpression, immunoblotting, immunoprecipitation, 
      immunohistochemistry, and in situ proximal ligation assays, to investigate the 
      function of dual-specificity tyrosine phosphorylation-regulated kinase 1A 
      (DYRK1A) in IRS-1 regulation and the downstream insulin signaling in neurons. We 
      found that DYRK1A overexpression up-regulated IRS-1 expression by slowing 
      turnover of the IRS-1 protein. We further observed that DYRK1A directly 
      interacted with IRS-1 and phosphorylated IRS-1's multiple serine residues. Of 
      note, DYRK1A and IRS-1 were coordinately up-regulated in the prefrontal cortex of 
      db/db mice brain. Furthermore, DYRK1A overexpression ameliorated chronic high 
      insulin-induced insulin resistance in SH-SY5Y cells as well as in primary rat 
      neurons. These findings suggest that DYRK1A protects against insulin resistance 
      in the brain by elevating IRS-1 expression.
CI  - (c) 2019 Tian et al.
FAU - Tian, Shijiao
AU  - Tian S
AD  - Department of Neurology, Qilu Hospital of Shandong University, No. 107 Wenhuaxi 
      Rd., 250012 Jinan, China.
AD  - Brain Research Institute, Qilu Hospital of Shandong University, No. 107 Wenhuaxi 
      Rd., 250012 Jinan, China.
FAU - Jia, Wenming
AU  - Jia W
AD  - NHC Key Laboratory of Otorhinolaryngology, Chinese Ministry of Health, Qilu 
      Hospital of Shandong University, No. 44 Wenhuaxi Rd., 250012 Jinan, China.
FAU - Lu, Mei
AU  - Lu M
AD  - Department of Geriatrics, Qilu Hospital of Shandong University, No. 107 Wenhuaxi 
      Rd., 250012 Jinan, China.
FAU - Zhao, Juan
AU  - Zhao J
AD  - NHC Key Laboratory of Otorhinolaryngology, Chinese Ministry of Health, Qilu 
      Hospital of Shandong University, No. 44 Wenhuaxi Rd., 250012 Jinan, China.
FAU - Sun, Xiulian
AU  - Sun X
AD  - Brain Research Institute, Qilu Hospital of Shandong University, No. 107 Wenhuaxi 
      Rd., 250012 Jinan, China xiulians@gmail.com.
AD  - The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese 
      Ministry of Education, Chinese National Health Commission, Qilu Hospital of 
      Shandong University, No. 107 West Wenhua Rd., Jinan, 250012 Shandong Province, 
      China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20191113
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Insulin)
RN  - 0 (Insulin Receptor Substrate Proteins)
RN  - 0 (Irs1 protein, mouse)
RN  - 98600C0908 (Cycloheximide)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Cell Line, Tumor
MH  - Cycloheximide/pharmacology
MH  - Diabetes Mellitus, Type 2/metabolism/pathology
MH  - Disease Models, Animal
MH  - Humans
MH  - Insulin/metabolism/pharmacology
MH  - Insulin Receptor Substrate Proteins/*metabolism
MH  - Insulin Resistance
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Neurons/cytology/drug effects/*metabolism
MH  - Phosphorylation
MH  - Prefrontal Cortex/metabolism
MH  - Protein Serine-Threonine Kinases/genetics/*metabolism
MH  - Protein-Tyrosine Kinases/genetics/*metabolism
MH  - Rats
MH  - Signal Transduction
MH  - Ubiquitination
MH  - Up-Regulation/drug effects
MH  - Dyrk Kinases
PMC - PMC6937568
OTO - NOTNLM
OT  - Alzheimer disease
OT  - DYRK1A
OT  - brain neuron
OT  - db/db mouse
OT  - diabetes
OT  - insulin receptor substrate 1 (IRS-1)
OT  - insulin resistance
OT  - metabolic disorder
OT  - neurodegenerative disease
COIS- The authors declare that they have no conflicts of interest with the contents of 
      this article
EDAT- 2019/11/15 06:00
MHDA- 2020/06/23 06:00
PMCR- 2019/11/13
CRDT- 2019/11/15 06:00
PHST- 2019/08/26 00:00 [received]
PHST- 2019/11/10 00:00 [revised]
PHST- 2019/11/15 06:00 [pubmed]
PHST- 2020/06/23 06:00 [medline]
PHST- 2019/11/15 06:00 [entrez]
PHST- 2019/11/13 00:00 [pmc-release]
AID - S0021-9258(20)30033-8 [pii]
AID - RA119.010809 [pii]
AID - 10.1074/jbc.RA119.010809 [doi]
PST - ppublish
SO  - J Biol Chem. 2019 Dec 27;294(52):20164-20176. doi: 10.1074/jbc.RA119.010809. Epub 
      2019 Nov 13.