Disease relevance of NUMB

• The recombinant hNumb expressed in Sf-9 cells using baculovirus protein expression system bound to Mdm2 in vitro [1].
• Conversely, Numb silencing increases Notch signaling in normal breast cells and in Numb-positive breast tumors [2].
• A role for Notch signaling in human breast cancer has been suggested by both the development of adenocarcinomas in the murine mammary gland following pathway activation and the loss of Numb expression, a negative regulator of the Notch pathway, in a large proportion of breast carcinomas [3].
• Characterization of human LNX, a novel ligand of Numb protein X that is downregulated in human gliomas [4].

High impact information on NUMB

• This resulted in severe damage to brain lateral ventricle integrity and identified roles for Numb/Numblike in regulating ependymal wall integrity and SVZ neuroblast survival [5].
• We demonstrate that the Hedgehog transcription factor Gli1 is targeted by Numb for Itch-dependent ubiquitination, which suppresses Hedgehog signals, thus arresting growth and promoting cell differentiation [6].
• CRMP-2 regulates polarized Numb-mediated endocytosis for axon growth [7].
• We found that Numb was associated with L1, a neuronal cell adhesion molecule that is endocytosed and recycled at the growth cone, where CRMP-2 and Numb were colocalized [7].
• These results suggest that in addition to regulating microtubule assembly, CRMP-2 is involved in polarized Numb-mediated endocytosis of proteins such as L1 [7].

Biological context of NUMB

• Thus, the Numb/Notch biological antagonism is relevant to the homeostasis of the normal mammary parenchyma and its subversion contributes to human mammary carcinogenesis [2].
• Experiments using dominant-negative constructs and RNA interference insure that Numb is necessary for the LNX1-mediated endocytosis of JAM4 [8].
• The presence of multiple protein binding domains involved in signal transduction and interaction with Numb and SKIP suggested an important role for LNX in tumorogenesis [4].
• aPKC-mediated phosphorylation regulates asymmetric membrane localization of the cell fate determinant Numb [9].
• These results suggest a model in which phosphorylation of Numb by aPKC regulates its polarized distribution in epithelial cells as well as during asymmetric cell divisions [9].

Anatomical context of NUMB

• We found that Numb localizes to endocytic organelles and is cotrafficked with internalizing receptors [10].
• These results highlight a role of Numb for dendritic spine development and synaptic functions with intersectin and EphB2 [11].
• We showed that inhibition of Notch activity by either overexpressing Numb or by using a pharmacological gamma-secretase inhibitor (DAPT) enhanced differentiation of murine and human myoblasts [12].
• In epithelial cells, mammalian Numb localizes to the basolateral membrane and is excluded from the apical domain, which accumulates aPKC [9].
• In addition to the previously described association of the PTB domain with the plasma membrane, we show that the AP2-binding motifs facilitate the association of Numb with cortical membrane punctae and vesicles [13].

Associations of NUMB with chemical compounds

• Furthermore, Numb formed a complex with EphB2 receptor-type tyrosine kinase and NMDA-type glutamate receptors [11].
• The expression of myogenin (baseline, 6.2 vs. 20.7% after treatment, P < 0.005), examined only in the 300-mg group, increased significantly in muscle fiber nuclei after testosterone treatment, but Numb expression did not change [14].
• This effect is correlated with Numb phosphorylation and an increase in its Triton X-100 solubility [13].

Physical interactions of NUMB

• The Mdm2 oncoprotein interacts with the cell fate regulator Numb [15].
• The function of Numb has been linked to its ability to bind and to biologically antagonize Notch, a membrane receptor that also specifies cell fate [10].

Regulatory relationships of NUMB

• Knockdown of Numb suppressed the ephrin-B1-induced spine development and maturation [11].

Other interactions of NUMB

• Human homologue of Numb (hNumb) was cloned as Mdm2-binding protein by yeast two-hybrid screening [1].
• Here, we identify the RING-type E3 ubiquitin ligase LNX (ligand of Numb protein X) as an Np9-interacting partner [16].
• Many intracellular proteins, such as Fe65, Jip-1, Shc, Numb and X11alpha, interact with AID and modulate its function by different mechanisms [17].
• Junctional adhesion molecule 4, LNX1 and Numb form a tripartite complex in vitro and are partially colocalized in heterologous cells [8].

References