The Multitasker Protein: A Look at the Multiple Capabilities of NUMB

Abstract

NUMB, a plasma membrane-associated protein originally described in Drosophila, is involved in determining cell function and fate during early stages of development. It is secreted asymmetrically in dividing cells, with one daughter cell inheriting NUMB and the other inheriting its antagonist, NOTCH. NUMB has been proposed as a polarizing agent and has multiple functions, including endocytosis and serving as an adaptor in various cellular pathways such as NOTCH, Hedgehog, and the P53-MDM2 axis. Due to its role in maintaining cellular homeostasis, it has been suggested that NUMB may be involved in various human pathologies such as cancer and Alzheimer's disease. Further research on NUMB could aid in understanding disease mechanisms and advancing the field of personalized medicine and the development of new therapies.

Keywords: Alzheimer; NUMB; cancer; development; isoforms; neurogenesis.

Figure 1

NUMB isoforms are generated by alternative splicing, being the PTB and PRR domains involved in this process. The resulting isoforms can be classified as having long or short PTB (PTB^L/S) and long or short PRR (PRR^L/S) domains. Please note that the sizes of exons and domains in the diagram are not to scale and are simplified for clarity.

Figure 2

(A) NUMB and NOTCH are asymmetrically distributed to daughter cells during SOPs in Drosophila. (B) NUMB and NOTCH are involved in determining cell fate in Drosophila neuroblasts. The cell that inherits NOTCH (Neuroblast) has self-renewal properties, while the cell that inherits NUMB (GMC: ganglion mother cell) is able to differentiate into neurons. (C) The balance of NUMB and NOTCH is also thought to be involved in EMT in mice and humans tumors. Increased NUMB expression relative to NOTCH has been shown to reduce EMT, while increased NOTCH levels can increase EMT.

Figure 3

NUMB acts as an adaptor protein in multiple signaling pathways. NUMB inhibits NOTCH signaling by interacting with NICD. Additionally, the interaction between NUMB and MDM2 increases p53 stability, allowing transcription of genes related to DNA-damage repair. Furthermore, the PRR^L NUMB isoform promotes ERK/MAPK signaling and the formation of a SMAD complex, leading to transcription of genes related to EMT. In addition, NUMB promotes the ubiquitination and subsequent degradation of both NUMB and ITCH through GLI1.