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PDBsum entry 5bo1
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Signaling protein/immune system
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PDB id
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5bo1
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Contents |
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150 a.a.
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213 a.a.
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214 a.a.
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References listed in PDB file
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Key reference
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Title
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Therapeutic antibodies reveal notch control of transdifferentiation in the adult lung.
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Authors
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D.Lafkas,
A.Shelton,
C.Chiu,
G.De leon boenig,
Y.Chen,
S.S.Stawicki,
C.Siltanen,
M.Reichelt,
M.Zhou,
X.Wu,
J.Eastham-Anderson,
H.Moore,
M.Roose-Girma,
Y.Chinn,
J.Q.Hang,
S.Warming,
J.Egen,
W.P.Lee,
C.Austin,
Y.Wu,
J.Payandeh,
J.B.Lowe,
C.W.Siebel.
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Ref.
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Nature, 2015,
528,
127-131.
[DOI no: ]
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PubMed id
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Abstract
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Prevailing dogma holds that cell-cell communication through Notch ligands and
receptors determines binary cell fate decisions during progenitor cell
divisions, with differentiated lineages remaining fixed. Mucociliary clearance
in mammalian respiratory airways depends on secretory cells (club and goblet)
and ciliated cells to produce and transport mucus. During development or repair,
the closely related Jagged ligands (JAG1 and JAG2) induce Notch signalling to
determine the fate of these lineages as they descend from a common proliferating
progenitor. In contrast to such situations in which cell fate decisions are made
in rapidly dividing populations, cells of the homeostatic adult airway
epithelium are long-lived, and little is known about the role of active Notch
signalling under such conditions. To disrupt Jagged signalling acutely in adult
mammals, here we generate antibody antagonists that selectively target each
Jagged paralogue, and determine a crystal structure that explains selectivity.
We show that acute Jagged blockade induces a rapid and near-complete loss of
club cells, with a concomitant gain in ciliated cells, under homeostatic
conditions without increased cell death or division. Fate analyses demonstrate a
direct conversion of club cells to ciliated cells without proliferation, meeting
a conservative definition of direct transdifferentiation. Jagged inhibition also
reversed goblet cell metaplasia in a preclinical asthma model, providing a
therapeutic foundation. Our discovery that Jagged antagonism relieves a blockade
of cell-to-cell conversion unveils unexpected plasticity, and establishes a
model for Notch regulation of transdifferentiation.
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