PIAS family

A number of proteins that inhibit the JAK-STAT function have also been identified. These include members of the so-called SOCS/Jab/Cis family and the PIAS family of regulatory proteins. Several appear to function by inhibiting the activation of various STATs, although the mechanisms by which this is achieved remain to be elucidated in detail. The JAK-STAT pathway likely does not function in isolation within the cell. JAKs are believed to activate elements of additional signalling pathways, and STATs are also likely activated by factors other than JAKs. As such, there may be considerable crosstalk between various JAK- and/or STAT-dependent signalling pathways. 

Jackson, P.K. 2001. A new RING for SUMO wrestling transcriptional responses into nuclear bodies with PIAS family E3 SUMO ligases. Genes Dev. 15, 3053-3058. 

STATs are also inactivated. The protein inhibitors of activated STAT (PIAS) family of proteins bind to phosphorylated STATs and prevent their dimerization or promote the dissociation of STAT dimers. STATs also may be inactivated by dephosphorylation, although the specific phosphatases have not yet been identified, or by targeting activated STATs for proteolytic degradation. 

PIAS (protein inhibitors of activated STATs) proteins were first discovered in yeast-two-hybrid screens as interacting molecules with STAT transcription factors. The mammalian family consists ofthe founding member PIAS3, which was described as a repressor of STAT3, and three additional members, PIAS1, PIASy (also known as PIAS4), and PIASx (also known as... 

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Pyrrole 2-aminoimidazole alkaloids (PIAs) represent one of the most important groups of sponge secondary metabolites which show a large panel of biological activities [308]. Marine sponges, specifically the Agelasidae and Leucetta families, are the primary sources of structurally diverse secondary metabolites containing a 2-aminoimidazole functionality. Oroidin, isolated in 1971 by Forenza et al., was the first discovered member of this alkaloid family, and since then nearly 150 additional natural products have been isolated [309, 310]. 

Although the number of studies using (radio) labeled substrates in an attempt to confirm the generation of these PIAs in nature is limited, numerous biosynthetic hypotheses occupy the chemical/synthetic literature [34, 35]. These proposals represent all levels of the complexity spectrum for this family, from simple cyclic compounds derived from an oroidin monomer to those that result from dimerization of oroidin and further cyclizations. To prevent this chapter from occupying the whole book, only two examples will be presented in this subsection to serve as a general overview. 

Baran also postulated that these simpler dimeric PIAs could be precursors to the more advanced tetracyclic and hexacyclic family members. Key to this hypothesis was the common putative intermediate pre-axinellamine (139), which hypothetically could be produced from both the rearrangement of sceptrin (66) or ageliferin (132) (Schane 13.22) [114]. Oxidative ring expansion (sceptrin) or contraction (ageliferin) induced by either electrophilic oxygen or chlorine, respectively, would lead to formation of the highly functionalized cyclopentane core (137) of this hypothetical compound. Eurther oxidation of the aminoimidazole would then yield pre-axinellamine (139). 

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