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McGlade Lab

Numb

Characterization of mammalian Numb

During development cells within the organism become increasingly specialized in order to form the organs and structures of the adult organism. To facilitate this, critical decisions are made at the molecular level during cell division. Often these decisions are mediated by proteins which are defined as cell fate determinants. The protein Numb was originally identified in the fruit fly as a mutation that removed sensory neurons. This abnormality was subsequently found to be caused by a shift in cell fate.

The exact mechanism of how Numb influences cell fate is unknown, however evidence suggests it down-regulates or decreases the activity of another cell fate determinant, the Notch receptor. Mutations in cell fate pathways have been previously linked to human malignancies, for example uncontrolled activation of Notch has been observed in leukemias and breast cancer. While the function of mammalian Numb is unknown, we know the Numb protein contains protein interaction surfaces suggesting Numb may function by forming a protein scaffold in the cell to regulate signaling events.

Previously, our lab has shown that Numb binds to proteins involved in cell surface protein internalization (endocytosis) and degradation and may function to link these two processes. Both endocytosis and protein degradation are critical to normal cell function and when disrupted can lead to prolonged receptor activation and oncogenesis. Ongoing projects in the lab include studies on how Numb is regulated by phosphorylation and ubiquitination during the internalization and trafficking of receptors.