Notch transmembrane receptors direct essential cellular processes, such as 
proliferation and differentiation, through direct cell-to-cell interactions. 
Inappropriate release of the intracellular domain of Notch (N(ICD)) from the 
plasma membrane results in the accumulation of deregulated nuclear N(ICD) that 
has been linked to human cancers, notably T-cell acute lymphoblastic leukemia 
(T-ALL). Nuclear N(ICD) forms a transcriptional activation complex by 
interacting with the coactivator protein Mastermind-like 1 and the DNA binding 
protein CSL (for CBF-1/Suppressor of Hairless/Lag-1) to regulate target gene 
expression. Although it is well understood that N(ICD) forms a transcriptional 
activation complex, little is known about how the complex is assembled. In this 
study, we demonstrate that N(ICD) multimerizes and that these multimers function 
as precursors for the stepwise assembly of the Notch activation complex. 
Importantly, we demonstrate that the assembly is mediated by N(ICD) multimers 
interacting with Skip and Mastermind. These interactions form a preactivation 
complex that is then resolved by CSL to form the Notch transcriptional 
activation complex on DNA.