Term Count P value Genes MAPK signaling pathway 13 0.0062 RPS6KA5, AKT1, MAP4K4, MAP3K5, PLA2G4A, DUSP2, FGF9, TGFBR1, MAP2K4, MKNK2, PPP3R1, FGF12, DUSP6 Endocytosis 10 0.010 IGF1R, ADRB3, FLT1, TGFBR1, PSD3, VPS4B, DNAJC6, PSD2, ARAP2, LDLRAP1 Axon guidance 7 0.042 EPHA5, SEMA6A, PLXNA1, PPP3R1, SEMA4C, L1CAM, SRGAP1 Insulin signaling 6 0.0076 AKT1, L1CAM, IGF1R, IRS2, pathway SOCS7
, RHOQ Focal adhesion 4 0.021 VCAM1, L1CAM, ITGA4, CERCAM Table 2: Small molecules which might reverse the dysregulation of AD in EC and HIP regions.
Indeed, CIS and SOCS2, SOCS1 and SOCS3, SOCS4 and SOCS5, and SOCS6 and SOCS7 all form related pairs .
For example, CIS, SOCS1, SOCS2, and SOCS3 have relatively short (50-80 residues) N-terminal regions, whereas SOCS4, SOCS5, SOCS6 and SOCS7 have longer N-terminal regions of up to 380 residues [22, 25, 26].
Most striking are the extended N-terminal regions of SOCS4 (270 aa), SOCS5 (368 aa), SOCS6 (369 aa), and SOCS7 (385 aa) (excluding the ESS), suggesting these four proteins form a subgroup within the SOCS family.
In Vitro Functions of SOCS6 and SOCS7. Like other SOCS proteins, SOCS6 likely primary regulatory role is through ubiquitination
and degradation of target proteins , using specific interaction with an alternate E3 ligase component named heme-oxidised IRP2 ubiquitin ligase-1 (HOIL-1) , and as SOCS2, SOCS6 also has the ability to degrade other SOCS proteins, including SOCS7 .
SOCS7 was first identified through its ability to interact with the SH3 domain of the adaptor protein Nck and is unique in its possession of a proline-rich N-terminal domain and nuclear localisation motif .
SOCS7 can interact with Grb2 at this level [27, 130, 171].
Deletion of the SOCS7 gene had a more dramatic effect, resulting in premature death due to hydrocephalus in C57BL/6 mice, with no obvious defects in glucose homeostasis.
Interestingly, SOCS3 represents a good example that SOCS family tumour suppressor activity may not be solely due to their negative feedback role in the JAKSTAT signalling (the other examples are SOCS6 and SOCS7; see below).
Similar to SOCS1 and SHP1, [STAT6.sup.high] HT-29 cells expressed low constitutive mRNA of SOCS3 and SOCS7 than [STAT6.sup.null] colonic cancer Caco-2 cells .