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Updated: Mar 9, 2026

Studying Cell Cycle-regulated Gene Expression by Two Complementary Cell Synchronization Protocols
12:02

Studying Cell Cycle-regulated Gene Expression by Two Complementary Cell Synchronization Protocols

Published on: June 6, 2017

28.6K

Adaptor proteins NUMB and NUMBL promote cell cycle withdrawal by targeting ERBB2 for degradation

Maretoshi Hirai, Yoh Arita, C Jane McGlade

    The Journal of Clinical Investigation
    |January 10, 2017
    PubMed

    Insights

    NUMB and NUMBL proteins are crucial for heart development, preventing ventricular noncompaction by downregulating ERBB2 signaling. Their loss sustains ERBB2 signaling, leading to abnormal cardiomyocyte proliferation and heart failure.

    Area of Science:

    • Cardiovascular Biology
    • Cellular Mechanisms of Heart Development
    • Molecular Cardiology

    Background:

    • Trabecular myocyte cell cycle withdrawal is essential for preventing ventricular noncompaction and heart failure.
    • ERBB2 (Epidermal Growth Factor Receptor 2) signaling is vital for myocyte proliferation and cardiac trabeculation.
    • Mechanisms regulating ERBB2 signaling downregulation in developing hearts are not fully understood.

    Purpose of the Study:

    • To investigate the role of endocytic adaptor proteins NUMB and NUMBL in regulating ERBB2 signaling.
    • To elucidate the molecular pathways linking NUMB/NUMBL to cardiomyocyte cell cycle control.
    • To understand the implications for ventricular noncompaction cardiomyopathy.

    Main Methods:

    • Utilized genetic models to study the function of NUMB and NUMBL in cardiac development.
    • Investigated ERBB2 signaling dynamics, endosome trafficking, and STAT5/YAP1 activation.
    • Assessed the impact of genetic alterations on cardiomyocyte proliferation and ventricular morphology.

    Main Results:

    • Loss of NUMB and NUMBL impaired late endosome formation, causing sustained ERBB2 signaling and STAT5 activation.
    • Activated STAT5 bypassed Hippo pathway inhibition, promoting YAP1 nuclear translocation and aberrant cardiomyocyte proliferation.
    • Ventricular noncompaction was significantly rescued by reducing ERBB2 or YAP1 levels.
    • NUMB and NUMBL facilitate ERBB2 degradation via interaction with Rab7.

    Conclusions:

    • NUMB and NUMBL are critical for ERBB2 signaling downregulation, promoting cardiomyocyte cell cycle exit.
    • Aberrant activation of ERBB2-STAT5-YAP1 signaling contributes to ventricular noncompaction.
    • These findings reveal novel connections between cell cycle regulation pathways with implications for heart failure and regenerative medicine.

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