HES and HERP families: Multiple effectors of the notch signaling pathway

Authors

  • Tatsuya Iso,

    1. Institute for Genetic Medicine, Department of Biochemistry and Molecular Biology, Keck School of Medicine of the University of Southern California, Los Angeles, California
    Current affiliation:
    1. Second Department of Internal Medicine, Gunma University School of Medicine, Gunma 371-8511, Japan
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  • Larry Kedes,

    Corresponding author
    1. Institute for Genetic Medicine, Department of Biochemistry and Molecular Biology, Keck School of Medicine of the University of Southern California, Los Angeles, California
    2. Department of Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, California
    • 2250 Alcazar Street, Los Angeles, California 90089, USA.
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  • Yasuo Hamamori

    Corresponding author
    1. Center for Cardiovascular Development, Department of Medicine, and Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas
    • One Baylor Plaza, 506D, Houston, Texas 77030, USA.
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Abstract

Notch signaling dictates cell fate and critically influences cell proliferation, differentiation, and apoptosis in metazoans. Multiple factors at each step—ligands, receptors, signal transducers and effectors—play critical roles in executing the pleiotropic effects of Notch signaling. Ligand-binding results in proteolytic cleavage of Notch receptors to release the signal-transducing Notch intracellular domain (NICD). NICD migrates into the nucleus and associates with the nuclear proteins of the RBP-Jκ family (also known as CSL or CBF1/Su(H)/Lag-1). RBP-Jκ, when complexed with NICD, acts as a transcriptional activator, and the RBP-Jκ-NICD complex activates expression of primary target genes of Notch signaling such as the HES and enhancer of split [E(spl)] families. HES/E(spl) is a basic helix-loop-helix (bHLH) type of transcriptional repressor, and suppresses expression of downstream target genes such as tissue-specific transcriptional activators. Thus, HES/E(spl) directly affects cell fate decisions as a primary Notch effector. HES/E(spl) had been the only known effector of Notch signaling until a recent discovery of a related but distinct bHLH protein family, termed HERP (HES-related repressor protein, also called Hey/Hesr/HRT/CHF/gridlock). In this review, we summarize the recent data supporting the idea of HERP being a new Notch effector, and provide an overview of the similarities and differences between HES and HERP in their biochemical properties as well as their tissue distribution. One key observation derived from identification of HERP is that HES and HERP form a heterodimer and cooperate for transcriptional repression. The identification of the HERP family as a Notch effector that cooperates with HES/E(spl) family has opened a new avenue to our understanding of the Notch signaling pathway. © 2003 Wiley-Liss, Inc.

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