Notch: Implications of endogenous inhibitors for therapy.
Soluble components of Notch signalling can be applied to manipulate a central pathway essential for the development of metazoans and often deregulated in illnesses such as stroke, cancer or cardiovascular diseases. Commonly, the Notch cascade is inhibited by small compound inhibitors, which either block the proteolysis of Notch receptors by gamma-secretases or interfere with the transcriptional activity of the Notch intracellular domain. Specific antibodies can also be used to inhibit ligand-induced activation of Notch receptors. Alternatively, naturally occurring endogenous inhibitors of Notch signalling might offer a specific way to block receptor activation. Examples are the soluble variants of the canonical Notch ligand Jagged1 and the non-canonical Notch ligand Dlk1, both deprived of their transmembrane regions upon ectodomain shedding, or the bona fide secreted molecule EGFL7. We present frequently used methods to decrease Notch signalling, and we discuss how soluble Notch inhibitors may be used to treat diseases.
Dikic
Ivan
I
Frankfurt Institute for Molecular Life Sciences (FMLS) and Institute of Biochemistry II, Johann Wolfgang Goethe University School of Medicine, Frankfurt am Main, Germany.
Schmidt
Mirko H H
MHH
Molecular Signal Transduction, Institute of Neurology (Edinger Institute), Johann Wolfgang Goethe University School of Medicine, Frankfurt am Main, Germany.
D000818:Animals; D002135:Calcium-Binding Proteins; D004358:Drug Therapy / Q000379:methods*; D066255:EGF Family of Proteins; D016228:Endothelial Growth Factors / Q000378:metabolism / Q000627:therapeutic use; D006801:Humans; D009474:Neurons / Q000166:cytology; D051880:Receptors, Notch / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects
D002135:Calcium-Binding Proteins; D066255:EGF Family of Proteins; C527877:EGFL7 protein, human; D016228:Endothelial Growth Factors; D051880:Receptors, Notch