Moving forward the new mathematical model opens doors
Moving forward, the new mathematical model opens doors for understanding the SCF network, where activity of a component is blunted through mutation or altered in expression in diseased states, and during therapeutic intervention. Computational modeling could reveal underappreciated secondary or tertiary effects of network perturbation and how these might contribute to disease. It will also be interesting to see how CAND-driven exchange functions, and to what extent it is required, in organisms like C. elegans and D. melanogaster that express multiple Skp1-related genes with divergent sequences in CUL1-binding loops that prevent simultaneous binding to CAND1. With the availability of an accurate mathematical model, these and other mysteries of SCF and CRL networks CAN(D) now be solved.
Itch regulates immune cell function to prevent autoimmune disease Most of the evidence surrounding the role of Itch in immune mmp inhibitor supports the idea that Itch promotes peripheral tolerance. Less is known about how Itch may regulate immune cell development and central tolerance. There is some evidence that Itch regulates hematopoiesis and B cell development ,  but it is not clear if this impacts central tolerance mechanisms and selection of the TCR and BCR repertoires. After lymphocyte development, it is evident that Itch is involved at multiple stages in autoimmune disease, preventing an initial break in tolerance, then shaping the subsequent inflammatory processes that occur. Itch prevention of autoimmunity is dependent on its enzymatic function. Most of the molecular evidence for Itch ubiquitylation of substrates originates from overexpression systems in cell lines. Many substrates have been identified using this approach, but it remains unclear to what extent these mechanisms prevent the emergence and exacerbation of autoimmunity in vivo. In contrast, studies that used primary immune cells and that measure endogenous (i.e. not overexpressed) enzyme/substrate relationships provide stronger evidence for physiologically relevant Itch activities that might prevent autoimmunity. As we review the roles of Itch in immune cells, we also note the experimental systems that were used to define molecular substrates of Itch. Additionally, we discuss cellular pathways and substrates regulated by Itch in non-immune cells. Defining different Itch-dependent regulatory networks could allow for therapeutic targeting of specific aspects of Itch function that could be used to treat autoimmune disease.
Molecular regulation of itch enzymatic activity Itch is a catalytic E3 ubiquitin ligase. Itch exists in an inactive state, mediated by intramolecular interactions. The WW domains of Itch bind to its catalytic HECT domain, preventing Itch from ubiquitylating substrates. Therefore, Itch must first be activated, through relief of intramolecular inhibition, in order to ubiquitylate its substrates. Itch enzymatic activity can be regulated by phosphorylation as well as protein-protein interactions. Most of the molecular regulators of Itch have been identified using ubiquitylation of the substrate JunB as the readout for Itch activity, but distinct activators have also been shown to regulate additional substrates in non-T cells, including CXCR4 and cFLIP. It is unknown why multiple mechanisms for Itch activation exist, but one possibility is that distinct activation mechanisms allow ubiquitylation of different substrates and in different cell types.
Perspective on itch regulatory networks and therapeutic targeting The mechanisms governing Itch function in T cells are the most well-defined. Both Ndfip1 and JNK phosphorylation can activate Itch in T cells by relieving Itch autoinhibition through a conformational change, and tyrosine phosphorylation can inhibit Itch , , . So far, both Ndfip1 and JNK can activate Itch to degrade JunB in T cells, but only Ndfip1 has been shown to promote ubiquitylation of RORγt, and Jak1 , , , , . Tax1bp1 has also been shown to activate Itch in T cells, promoting its association with the ubiquitin editing enzyme A20 and degradation of a Rip1 to dampen NFκB signaling, which was not shown to be regulated by either Ndfip1 or JNK in T cells.