Gigantism in mice lacking suppressor of cytokine signalling-2

Abstract

Suppressor of cytokine signalling-2 (SOCS-2) is a member of the suppressor of cytokine signalling family, a group of related proteins implicated in the negative regulation of cytokine action through inhibition of the Janus kinase (JAK) signal transducers and activators of transcription (STAT) signal-transduction pathway. Here we use mice unable to express SOCS-2 to examine its function in vivo. SOCS-2(-/-) mice grew significantly larger than their wild-type littermates. Increased body weight became evident after weaning and was associated with significantly increased long bone lengths and the proportionate enlargement of most organs. Characteristics of deregulated growth hormone and insulin-like growth factor-I (IGF-I) signalling, including decreased production of major urinary protein, increased local IGF-I production, and collagen accumulation in the dermis, were observed in SOCS-2-deficient mice, indicating that SOCS-2 may have an essential negative regulatory role in the growth hormone/IGF-I pathway.

SOCS36E, a novel Drosophila SOCS protein, suppresses JAK/STAT and EGF-R signalling in the imaginal wing disc

“…Although SOCS36E is most closely related to SOCS-5, the fact that SOCS36E can suppress JAK/STAT signalling in flies makes it functionally related to CIS and SOCS-1 -3. SOCS-1 -3 have been shown to suppress c-kit (De Sepulveda et al, 1999), PDGF (Cacalano et al, 2001), insulin (Emanuelli et al, 2000) and IGF-I (Metcalf et al, 2000) signalling indicating that SOCS proteins also regulate several receptor tyrosine kinase pathways. This appears to also be true for SOCS36E as we show, in vivo, an interaction with EGF-R signalling in flies.…”

“…To date, much of the studies have focused on CIS and SOCS-1 -3. In addition to regulating JAK/STAT activity, they have been shown to suppress c-kit (De Sepulveda et al, 1999), PDGF (Cacalano et al, 2001), insulin (Emanuelli et al, 2000) and IGF-I (Metcalf et al, 2000) signalling and can facilitate the activation of the Ras/MAPK pathway (Cacalano et al, 2001). Their pleiotropic activity coupled with their wide tissue distribution (Hilton et al, 1998) suggest that SOCS proteins are general regulators of signalling pathways and will possess additional functions distinct from those already described.…”

Constitutive SOCS-3 expression protects T-cell lymphoma against growth inhibition by IFNα

“…Since the cloning of SOCS-1, it has become evident that SOCS are important for proper control of cytokine and growth factor responses and absence of SOCS proteins leads to excessive cytokine signaling. [8][9][10] In contrast to Stats, only little is known about SOCS protein involvement in cancer. Owing to their capability to inhibit Stat activation, SOCS proteins are likely to be dysregulated in cells with constitutive active Stat factors.…”

Constitutive expression of suppressor of cytokine signalling-3 in skeletal muscle leads to reduced mobility and overweight in mice

“…Thus, a significant decrease in Socs-2 and Cis was found. So far, SOCS-2 and CIS have been implicated mainly in regulating postnatal growth [34,35] and very little is known about their role in skeletal muscle metabolism. However, very recent data strongly suggest that SOCS-2 is a key actor in modulating insulin signal in muscle.…”