PMID- 38328115
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20240214
DP  - 2024 Jan 23
TI  - Myotubularin-related proteins regulate KRAS function by controlling plasma 
      membrane levels of polyphosphoinositides and phosphatidylserine.
LID - 2024.01.22.576612 [pii]
LID - 10.1101/2024.01.22.576612 [doi]
AB  - KRAS is a small GTPase, ubiquitously expressed in mammalian cells, that functions 
      as a molecular switch to regulate cell proliferation and differentiation. 
      Oncogenic mutations that render KRAS constitutively active occur frequently in 
      human cancers. KRAS must localize to the plasma membrane (PM) for biological 
      activity. KRAS PM binding is mediated by interactions of the KRAS membrane anchor 
      with phosphatidylserine (PtdSer), therefore, depleting PM PtdSer content 
      abrogates KRAS PM binding and oncogenic function. From a genome-wide siRNA screen 
      to search for genes that regulate KRAS PM localization, we identified a set of 
      phosphatidylinositol (PI) 3-phosphatase family members: myotubularin-related 
      (MTMR) proteins 2, 3, 4 and 7. Here we show that knockdown of MTMR 2/3/4/7 
      expression disrupts KRAS PM interactions. The molecular mechanism involves 
      depletion of PM PI 4-phosphate (PI4P) levels, which in turn disrupts the 
      subcellular localization and operation of oxysterol-binding protein related 
      protein (ORP) 5, a PtdSer lipid transfer protein that maintains PM PtdSer 
      content. Concomitantly, silencing MTMR 2/3/4/7 expression elevates PM levels of 
      PI3P and reduces PM and total cellular levels of PtdSer. In summary we propose 
      that the PI 3-phosphatase activity provided by MTMR proteins is required to 
      generate PM PI for the synthesis of PM PI4P, which in turn, promotes the PM 
      localization of PtdSer and KRAS.
FAU - Henkels, Karen M
AU  - Henkels KM
AD  - Department of Biochemistry and Molecular Biology, Boonshoft School of Medicine, 
      Wright State University, Dayton, Ohio 45435, USA.
FAU - Miller, Taylor E
AU  - Miller TE
AD  - Department of Biochemistry and Molecular Biology, Boonshoft School of Medicine, 
      Wright State University, Dayton, Ohio 45435, USA.
FAU - Naji, Ali
AU  - Naji A
AD  - Department of Diagnostic and Biomedical Sciences, School of Dentistry, The 
      University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
FAU - van der Hoeven, Ransome
AU  - van der Hoeven R
AD  - Department of Diagnostic and Biomedical Sciences, School of Dentistry, The 
      University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
FAU - Liang, Hong
AU  - Liang H
AD  - Department of Integrative Biology and Pharmacology, McGovern Medical School, 
      University of Texas Health Science Center, Houston, Texas 77030, USA.
FAU - Zhou, Yong
AU  - Zhou Y
AUID- ORCID: 0000-0002-0214-8151
AD  - Department of Integrative Biology and Pharmacology, McGovern Medical School, 
      University of Texas Health Science Center, Houston, Texas 77030, USA.
FAU - Hammond, Gerald R V
AU  - Hammond GRV
AUID- ORCID: 0000-0002-6660-3272
AD  - Department of Cell Biology, University of Pittsburgh School of Medicine, 
      Pittsburgh, PA 15213, USA.
FAU - Hancock, John F
AU  - Hancock JF
AD  - Department of Integrative Biology and Pharmacology, McGovern Medical School, 
      University of Texas Health Science Center, Houston, Texas 77030, USA.
FAU - Cho, Kwang-Jin
AU  - Cho KJ
AUID- ORCID: 0000-0002-2234-9292
AD  - Department of Biochemistry and Molecular Biology, Boonshoft School of Medicine, 
      Wright State University, Dayton, Ohio 45435, USA.
LA  - eng
GR  - R00 CA188593/CA/NCI NIH HHS/United States
GR  - R35 GM119412/GM/NIGMS NIH HHS/United States
PT  - Preprint
DEP - 20240123
PL  - United States
TA  - bioRxiv
JT  - bioRxiv : the preprint server for biology
JID - 101680187
PMC - PMC10849561
OTO - NOTNLM
OT  - 5-bisphosphate
OT  - KRAS
OT  - Myotubularin-related proteins
OT  - oxysterol-binding protein related protein (ORP) 5 and 8
OT  - phosphatidylinositol
OT  - phosphatidylinositol 3
OT  - phosphatidylinositol 3-phosphate
OT  - phosphatidylinositol 4-phosphate
OT  - phosphatidylserine
OT  - plasma membrane
EDAT- 2024/02/08 06:43
MHDA- 2024/02/08 06:44
PMCR- 2024/02/07
CRDT- 2024/02/08 04:15
PHST- 2024/02/08 06:43 [pubmed]
PHST- 2024/02/08 06:44 [medline]
PHST- 2024/02/08 04:15 [entrez]
PHST- 2024/02/07 00:00 [pmc-release]
AID - 2024.01.22.576612 [pii]
AID - 10.1101/2024.01.22.576612 [doi]
PST - epublish
SO  - bioRxiv [Preprint]. 2024 Jan 23:2024.01.22.576612. doi: 
      10.1101/2024.01.22.576612.