NOTCH signalointi keuhkojen pienissä tiehyeissä

LÄHDE: 
 Down-regulation of the Notch Pathway in HumanAirway Epithelium in Association with Smokingand Chronic Obstructive Pulmonary DiseaseAnn E. Tilley1, Ben-Gary Harvey1, Adriana Heguy2*, Neil R. Hackett2, Rui Wang2, Timothy P. O’Connor2, andRonald G. Crystal1,21Division of Pulmonary and Critical Care Medicine and2Department of Genetic Medicine, Weill Medical College of Cornell University,New York, New York

...  One such differentiation control system is the Notch signaling pathway. Originally discovered in Drosophila, there is evidencein experimental animals that the Notch pathway plays an important role in the determination of cell fate in multiple organsystems (7, 13, 15, 16) including the lung (7, 12–14). The classical role of Notch signaling is the prevention of cell differentiation and the maintenance of an undifferentiated state in stem cells invarious organs (7, 15, 37). 

When Notch is ‘‘on,’’ differentiation is suppressed,
 whereas when Notch is ‘‘off,’’ cells are allowed to proceed to a specific differentiation fate (13, 15, 16). 

Notch typically acts locally to define boundaries between different celltypes with divergent fates; for example, it can act following division of a stem cell to induce differentiation in one daughter cell and keep the other as a stem cell (13, 16). 
Notch signaling is simple in concept, but multiple regulatory components at every stage of the pathway add a level of complexity (13, 15–17).

 Notch signaling in humans is initiatedby interaction of one of the five Notch ligands, Delta-like (DLL1,3, or 4) or Jagged (JAG1 or 2) with one of the four receptors(NOTCH1, 2, 3, or 4). Both ligand and receptor are single-passmembrane proteins, and therefore Notch signaling typically involves cell-to-cell contact.



  Literature searches and Ingenuity Pathways software were used to identify components of the Notch signaling pathway, which were assigned to functional groups.Microarray data on small airway epithelial samples from the HG-U133 Plus 2.0 (n= 20 nonsmokers) were examined for the selected genes.†Expressed as P call percentage (%), which is defined as the percentage of normal nonsmoker samples for which the Affymetrix algorithm determined that the gene  was expressed or ‘‘Present’’ (P).‡Genes were categorized as expressed in human airway epithelium if the P call percentage was at least 50% in normal nonsmokers; for genes with more than one probe set, the percentage of P call listed is the highest value among the probe se


TABLE 2. NOTCH PATHWAY GENES EXPRESSED (%)  IN THE SMALL AIRWAY EPITHELIUM OF NONSMOKER (n=20)
LIGANDS  
 Delta-like ligand 1 , DLL1, 100, yes
 Delta-like ligand 3, DLL3,      5, no 
Delta-like ligand 4,  DLL4,       0, no 
Jagged 1,  JAG1,                100, yes
Jagged 2, JAG2          100  yes
RECEPTORS
Notch 1, NOTCH1      100, yes 
Notch 2, NOTCH2,      100, yes 
Notch 3, NOTCH3       100 , yes
 Notch 4, NOTCH4        90,  yes
PROTEASES
Disintegrin and metalloprotease 10,  ADAM10,   100, yes.
Disintegrin and metalloprotease 17, ADAM17, 100 yes.
Presenilin 1, PSEN1,   100, yes.
Presenilin 2, PSEN2,  100, yes.
Anterior pharynx defective 1 homolog,  AAPH1A,  100, yes.
Anterior pharynx defective 1 homolog,  BAPH1B,  100, yes.
Presenilin enhancer 2  homolog, PSENEN,    100, yes. 
 Nicastrin,  NCSTN, 100, yes.
TRANSCRIPTION FACTORS
 CBF1;
 CSL; 
recombining binding protein suppressor of hairless RBPSUH  100,  yes.
COACTIVATORS 
 Mastermind-like 1, MAML1,  100, yes.
 Mastermind-like 2,  MAML2,  100, yes.
 Mastermind-like 3,  MAML3,  100, yes.
 Lymphocyte-activation gene 3, LAG3,  5,  no.
Nuclear receptor co-repressor 2,  NCOR2,   100, yes.
DOWNSTREAM EFFECTORS
 Hairy & enhancer of split 1, HES1, 100,  yes.
Hairy & enhancer of split 2, HES2,  90, yes.
Hairy & enhancer of split 5, HES5,  50,  yes.
Hairy/enhancer-of-split related with YRPW motif 1,HEY1, 100, yes.
Hairy/enhancer-of-split related with YRPW motif 2, HEY2, 100, yes. 
Hairy/enhancer-of-split related with YRPW motif-like, HEYL, 90, yes. 
MODULATORS
Positive MODULATORS
Neuralized-like, NEURL,(RNF67,  RING Finger Protein 67   45, no.
Neuralized-like 2,  NEURL2 (Neuralized E3 Ubiquitin Protein Ligase 2),   0, no.
Mindbomb homolog 1, MIB1,( E3 ub ligase) ,ZZZ6, ZZANK2 100,  yes. (SARS2 nsp9 interaction protein)
Mindbomb homolog 2, MIB2,( ZZZ5),  100, yes. 
Protein O-fucosyltransferase 1, POFUT1,  40, no.
Protein O-fucosyltransferase 2,  POFUT2, 100, yes.
Ligand of numb-protein X,  LNX ,(RING-Type E3 Ubiquitin Transferase LNX;  PDZRN2), ,  100, yes.
Seven in absentia homolog 1, SIAH1,RINGtype E3 ubiquitin ligase,   100, yes.  
Musashi homolog 1, MSI1,    0, no. 
Musashi homolog 2, MSI2, 100, yes.
Dynamin 1, DNM1,   15, no.
Dynamin 2, DNM2,   95,  yes.
Dynamin 3, DNM3,  35, no.
Negative MODULATORS 
Hairy & enhancer of split 6, HES6,  95, yes.
 ITCHY homolog, ITCH, 100, yes.
 Neural precursor cell expressed, developmentally, down-regulated 4, NEDD4, 90, yes.
NUMB homolog, NUMB, 100, yes.
 Adaptor-related protein complex 2, a2 subunit [ora2]AP2A2,  100, yes.(SARS-2 nsp10 interaction protein)
 F-box & WD-40 protein 7, FBXW7, 100, yes.
SPEN homolog, SPEN, 100, yes.
MIXED/unknown MODULATORS
Radical fringe, RFNG, 90, yes.
 Lunatic fringe,LFNG, 60, yes.
 Manic fringe, MFNG, 75, yes.
Deltex homolog 1, DTX1, 0,no.
 Deltex homolog 2, DTX2, 100, yes, 
 Furin, FURIN, 75, yes.