*FBW7/hCDC4, an ubiquitin ligase, a substrate of E3,
It targets c-Myc, c-JUN and Notch for degradation through Ubiquitlation and proteasome degradation.
This is Mutated in grave cancer including Colon cancer and Acute lymphoblastic leukemia.
and of interest c-Myc is a critical Mediator of NOTCH activity.  Putting notch in epigenetic phenomena rather than at the membrane where it is said to drive cellular consensus !  Bad disease are determined to be bad here!

Notch1 involvement (and potentially the Wnt) determine the consensus to be bad in T-cell leukemia despite therapy. It is "a member of the Notch family. Members of this Type 1 transmembrane protein family share structural characteristics including an extracellular domain consisting of multiple epidermal growth factor-like (EGF) repeats, and an intracellular domain consisting of multiple, different domain types. Notch family members play a role in a variety of developmental processes by controlling cell fate decisions."(wikipedia)

Notch power is demonstrated by the fact that it induced Malformation (ie Bicuspid Aortic valve and Aortic Aneurysm). It is the Anti-apoptotic somewhat irreversible power of the Notch which makes this gene a dangerous contender for chemotherapeutic drugs (we suspect).  Researchers are now suggesting that p561ck could be the target to knock down in T-cell to affect the fate of these leukemic cells.   

Notch Cooperates with the Reelin pathway mainly in the brain
Notch has various co-factors (MAML1)
and acts on several promoters (HES) of genes (see Ankyrin)
Cross talk with Tumor Growth factors and Neurofactors

The NOTCH family of genes are "wild genes":

In a recent publication,

AIP4/Itch Regulates Notch Receptor Degradation in the Absence of Ligand

Patricia Chastagner, Alain Israël, and Christel Brou^{* et al put it this way}

" However it was recently shown that increased Notch signaling in transgenic mice mimics the symptoms of the disease [6]. Various substrates have been described for Itch in mammals: CXCR4 [7], p73, p63 [8], [9] smad 7 [10], Jun [11], Deltex (DTX, [12]) and Endophilin [13]. In general Itch targets its substrates to degradation, with some exceptions: AIP4 regulates the cell surface expression of select TRP channels by enhancing their ubiquitination and endocytosis but without facilitating their degradation [14]. Itch activity on junB is enhanced by Ser/Thr phosphorylation by MEKK1-JNK1 kinases [11], and reduced by Tyr phosphorylation in a fyn-dependent manner [15]. Thus it is difficult to attribute general characteristics to Itch, except that it is located in the endosomal system [7], [13], [16] and that it is autoubiquitinated [12], [17]. Furthermore the type of chains formed on its substrates is not often identified (except for K29-linked polyubiquitin chains on DTX and itself, [12]). Even less is known in Drosophila about the mechanisms controlled by Su(dx), Notch being its unique described target in this organism. Sakata et al. [18] have shown that ubiquitination of Drosophila Notch depends on Nedd4 (an E3 ubiquitin ligase belonging to the same family as Su(dx)) and on the presence of a PPSY motif in the intracellular region of Notch. Nedd4 is involved in the constitutive endocytosis of Notch and regulates its stability. Wilkin et al. [19] have demonstrated that Su(dx) and/or Nedd4 regulate sorting of Notch full-length within the early endosome. However these authors did not determine whether ubiquitination of Notch targets it for degradation, recycling or some other fate."

making the case for a "itch " to the NOTCH and to the variety of interactions that will take days to write about!

"IL-21-stimulated human plasmacytoid dendritic cells secrete granzyme B, which impairs their capacity to induce T-cell proliferation"  a new approach to treating ALL!