Activation of the NOTCH1 pathway in chronic lymphocytic leukemia.

328 haematologica | 2012; 97(3) Figure 1. Schematic representation of the NOTCH1 receptor. The extracellular domain of NOTCH1 consists of 36 epidermal growth factor-like repeats (EGFR) followed by 3 cysteine-rich lin12/Notch repeats (LNR) and the heterodimerization domain (HD). Upon transport to the plasmamembrane, NOTCH1 is cleaved in two units, which are kept together by interactions between the HD domains. Upon binding of the ligand, NOTCH1 is further cleaved by the gamma-secretase complex, resulting in release of the intracellular part (ICN1). ICN1 can then move to the nucleus where it functions in a transcriptional complex. ICN1 contains the RAM domain (R), ankyrine repeats, transactivation domain (TAD) and the PEST sequence that tags ICN1 for degradation by FBXW7. S2: proteolitic site for Metalloprotease; S3: gamma-secretase cleavage site. Activation of the NOTCH1 pathway in chronic lymphocytic leukemia