PMID- 22798074
OWN - NLM
STAT- MEDLINE
DCOM- 20121119
LR  - 20211203
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 287
IP  - 36
DP  - 2012 Aug 31
TI  - The E3 ubiquitin ligase protein associated with Myc (Pam) regulates 
      mammalian/mechanistic target of rapamycin complex 1 (mTORC1) signaling in vivo 
      through N- and C-terminal domains.
PG  - 30063-72
LID - 10.1074/jbc.M112.353987 [doi]
AB  - Pam and its homologs (the PHR protein family) are large E3 ubiquitin ligases that 
      function to regulate synapse formation and growth in mammals, zebrafish, 
      Drosophila, and Caenorhabditis elegans. Phr1-deficient mouse models (Phr1(Delta8,9) 
      and Phr1(Magellan), with deletions in the N-terminal putative guanine exchange 
      factor region and the C-terminal ubiquitin ligase region, respectively) exhibit 
      axon guidance/outgrowth defects and striking defects of major axon tracts in the 
      CNS. Our earlier studies identified Pam to be associated with tuberous sclerosis 
      complex (TSC) proteins, ubiquitinating TSC2 and regulating mammalian/mechanistic 
      target of rapamycin (mTOR) signaling. Here, we examine the potential involvement 
      of the TSC/mTOR complex 1(mTORC1) signaling pathway in Phr1-deficient mouse 
      models. We observed attenuation of mTORC1 signaling in the brains of both 
      Phr1(Delta8,9) and Phr1(Magellan) mouse models. Our results establish that Pam 
      regulates TSC/mTOR signaling in vitro and in vivo through two distinct domains. 
      To further address whether Pam regulates mTORC1 through two functionally 
      independent domains, we undertook heterozygous mutant crossing between Phr1(Delta8,9) 
      and Phr1(Magellan) mice to generate a compound heterozygous model to determine 
      whether these two domains can complement each other. mTORC1 signaling was not 
      attenuated in the brains of double mutants (Phr1(Delta8,9/Mag)), confirming that Pam 
      displays dual regulation of the mTORC1 pathway through two functional domains. 
      Our results also suggest that although dysregulation of mTORC1 signaling may be 
      responsible for the corpus callosum defects, other neurodevelopmental defects 
      observed with Phr1 deficiency are independent of mTORC1 signaling. The ubiquitin 
      ligase complex containing Pam-Fbxo45 likely targets additional synaptic and 
      axonal proteins, which may explain the overlapping neurodevelopmental defects 
      observed in Phr1 and Fbxo45 deficiency.
FAU - Han, Sangyeul
AU  - Han S
AD  - Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 
      02114, USA.
FAU - Kim, Sun
AU  - Kim S
FAU - Bahl, Samira
AU  - Bahl S
FAU - Li, Lin
AU  - Li L
FAU - Burande, Clara F
AU  - Burande CF
FAU - Smith, Nicole
AU  - Smith N
FAU - James, Marianne
AU  - James M
FAU - Beauchamp, Roberta L
AU  - Beauchamp RL
FAU - Bhide, Pradeep
AU  - Bhide P
FAU - DiAntonio, Aaron
AU  - DiAntonio A
FAU - Ramesh, Vijaya
AU  - Ramesh V
LA  - eng
GR  - P01 NS024279/NS/NINDS NIH HHS/United States
GR  - R01 DA020812/DA/NIDA NIH HHS/United States
GR  - DA020812/DA/NIDA NIH HHS/United States
GR  - NS024279/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20120713
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Carrier Proteins)
RN  - 0 (F-Box Proteins)
RN  - 0 (Fbxo45 protein, mouse)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Nerve Tissue Proteins)
RN  - 0 (Proteins)
RN  - 0 (TSC2 protein, human)
RN  - 0 (Tsc2 protein, mouse)
RN  - 0 (Tuberous Sclerosis Complex 2 Protein)
RN  - 0 (Tumor Suppressor Proteins)
RN  - EC 2.3.2.27 (Mycbp2 protein, mouse)
RN  - EC 2.3.2.27 (Ubiquitin-Protein Ligases)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Axons/*metabolism
MH  - Caenorhabditis elegans
MH  - Carrier Proteins/genetics/*metabolism
MH  - Corpus Callosum/metabolism
MH  - Drosophila
MH  - F-Box Proteins/genetics/metabolism
MH  - HEK293 Cells
MH  - Humans
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Mice
MH  - Mice, Mutant Strains
MH  - Multiprotein Complexes
MH  - Nerve Tissue Proteins/genetics/*metabolism
MH  - Protein Structure, Tertiary
MH  - Proteins/genetics/*metabolism
MH  - Signal Transduction
MH  - Synapses/genetics/*metabolism
MH  - TOR Serine-Threonine Kinases
MH  - Tuberous Sclerosis Complex 2 Protein
MH  - Tumor Suppressor Proteins/genetics/metabolism
MH  - Ubiquitin-Protein Ligases/genetics/*metabolism
MH  - Ubiquitination/physiology
PMC - PMC3436263
EDAT- 2012/07/17 06:00
MHDA- 2012/12/10 06:00
PMCR- 2013/08/31
CRDT- 2012/07/17 06:00
PHST- 2012/07/17 06:00 [entrez]
PHST- 2012/07/17 06:00 [pubmed]
PHST- 2012/12/10 06:00 [medline]
PHST- 2013/08/31 00:00 [pmc-release]
AID - S0021-9258(20)63111-8 [pii]
AID - M112.353987 [pii]
AID - 10.1074/jbc.M112.353987 [doi]
PST - ppublish
SO  - J Biol Chem. 2012 Aug 31;287(36):30063-72. doi: 10.1074/jbc.M112.353987. Epub 
      2012 Jul 13.