Mini review
Suppressor of cytokine signaling (SOCS) 2, a protein with multiple functions

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Abstract

Cytokine receptors act through a complex signaling network, involving Janus kinases (JAKs) and the signal transducers and activators of transcription (STATs), to regulate diverse biological processes which control growth, development, homeostasis and immune function, among others. The JAK/STAT signaling pathway is attenuated via three mechanisms controlling the initiation, magnitude, and duration of the signal: the PIAS proteins, which prevent STAT dimerization or DNA interaction, the SHP phosphatases, which dephosphorylate activating tyrosine phosphorylations, and the suppressors of cytokine signaling (SOCS), which are transcribed in response to cytokine stimulation and use several interconnected mechanisms to downregulate the signal. Specific studies targeting the SOCS genes in vivo have unveiled SOCS2 as the main regulator of somatic growth through regulation of GH/IGF-1 signaling. In addition, several studies indicate that SOCS2 also has important actions in the central nervous system, the regulation of metabolism, the immune response, the mammary gland development, cancer, and other cytokine-dependent signaling pathways. Consistent with the role of cytokines in human physiology, any SOCS2 imbalance could result in a broad range of pathologies such as cardiovascular diseases, insulin resistance, cancer, and severe infections, among others. Thus, determining the importance of SOCS2 in health and disease will no doubt aid in the development of novel therapeutic strategies. In this review, we attempt to summarize the available information, including our results, regarding the role of SOCS2 in several biological processes.

Introduction

Cytokines regulate a vast array of biological processes by activating cell surface receptor complexes. This process involves oligomerization and activation of the JAK family of tyrosine kinases, which in turn phosphorylate the receptor at specific tyrosine residues. STAT proteins are then recruited to these phosphorylated sites and are phosphorylated at tyrosine amino acids by the action of JAK proteins. Dimerization of the phosphorylated STATs leads to nuclear migration and regulation of gene expression [1]. To control excessive cytokine effects, the cytokine signal is negatively regulated by a number of proteins, including protein inhibitor of activated STAT (PIAS), protein tyrosine phosphatases, and suppressors of cytokine signaling (SOCS) [2], [3].

SOCS comprise a group of proteins that was identified in 1997 by different groups [4], [5], [6], [7]. To date, eight SOCS proteins have been cloned: cytokine-inducible SH2 containing protein (CIS), and SOCS1 through SOCS7 (Fig. 1). These proteins are characterized by a central SH2 domain, a conserved C-terminal domain named the SOCS box, and a variable N-terminal domain. A small kinase inhibitory region (KIR) is present in the N-terminal domain of SOCS1 and SOCS3 [8], [9]. SOCS proteins have been under intense scrutiny due to their ability to downregulate the cytokine-dependent JAK/STAT signaling pathway and thereby to control the cellular response to several cytokines and growth factors [10]. SOCS mRNA and protein levels are constitutively low in unstimulated cells, but their expression is rapidly induced upon cytokine stimulation, thereby creating a negative feedback loop. SOCS mechanisms of action rely on their ability to bind tyrosine phosphorylated proteins through their SH2 domains [8], but also to bind Elongin BC through their SOCS box domains [9]. SOCS proteins, when overexpressed in diverse cell lines, inhibit the action of a wide range of cytokines, observed as the reduction of both JAK and STAT activity [4], [5], [11]. SOCS can block cytokine signaling by acting as (i) kinase inhibitors of JAK proteins (SOCS1 and SOCS3), (ii) binding competitors against STATs (SOCS3 and CIS) and (iii) by acting as ubiquitin ligases, thereby promoting the degradation of their partners (SOCS1, SOCS3, and CIS).

The genetic manipulation of the SOCS genes in vivo has provided a more specific physiologic action for each of these proteins [12]. This is best exemplified by SOCS1 and SOCS3, whose main role has been related to the immune system, inflammatory diseases, and several cancers [13], [14]. Nevertheless, important functions are now emerging for other lesser known members of the family.

This review will discuss the multiple functions of SOCS2. This protein has mainly been linked to the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) signaling due the phenotype observed in mice lacking SOCS2 (SOCS2−/−). SOCS2-deficient (SOCS2−/−) mice are characterized by a 40% increase in body weight [15], a phenotype resembling that observed in GH transgenic mice [16], acromegalic patients [17], and high-growth (hg) mice [18]. The hg phenotype is the result of a spontaneous deletion within the chromosome 10, resulting in the inactivation of the socs2 locus [19]. Recently, Wong et al. have shown that the deletion occurs in the second exons of the socs2 and plexin C1 genes, resulting in formation of an expressed fusion transcript between socs2 and plexin C1 [20]. Several reports, including our own findings, indicate that SOCS2 not only regulates GH receptor signaling [21], [22], [23], but it might also have important actions in the regulation of other processes unique to somatic growth, such as metabolism, development of the central nervous system (CNS), cancer, the response to infection, and the regulation of other cytokine-dependent pathways, among others.

Section snippets

Regulation of SOCS2 gene expression

Although constitutively expressed SOCS2 mRNA has been detected in several tissues and cell types, its expression is, in general, induced by stimulation with different cytokines and hormones (Table 1). SOCS2 promoter analysis indicates the presence of four response elements within the promoter region that confer responsiveness to dioxin-treatment [24]. GH responsiveness in the SOCS2 promoter has not been reported yet, however strong evidence indicates that GH stimulation of SOCS2 expression is

Regulation of cytokine signaling by SOCS2

SOCS2, like the other members of the family, is able to regulate the cytokine-dependent JAK/STAT signaling pathway in several systems in vitro. SOCS2 has been associated with the regulation of GH, IGF-1, PRL, IL-2, IL-3, EPO, LIF, EGF, leptin and IFN-α-dependent signaling pathways, either positive or negative.

SOCS2 and metabolism

SOCS2−/− mice are giants but not obese [15]. A similar phenotype is also observed in the high-growth (hg) mutation, which is caused by a deletion of the socs2 locus [19]. By analysis of the hepatic gene expression profile and biochemical parameters in the SOCS2−/− mice, we have provided some insight into the action of SOCS2 in metabolism [21]. Our results indicate that SOCS2-deficient mice have some metabolic characteristics that can be related to the enhanced GH actions, such as decreased

SOCS2 and bone

SOCS2-deficient mice present a proportional enlargement of bone and muscle tissue, indicating that SOCS2 has a significant impact on skeletal components. However, analyses of SOCS2−/− bone mineral density (BMD) have revealed that the absence of SOCS2 induces a reduction in the trabecular and cortical volumetric BMD [57]. These results are in disagreement with an enhanced GH/IGF-1 signal, and suggest that the mechanism regulating BMD is GH-independent. Recently, it has been shown that SOCS2

SOCS2 and neural development

Several reports have revealed an important role for SOCS2 in neural development, growth, and stem cell differentiation. It has been shown that SOCS2 is highly expressed in the nervous system between embryonic day 10 (E10) and postnatal day 8 (P8), being maximal at day E14 which coincides with the peak of neuronal generation [59], [60]. Interestingly, the brain of the SOCS2−/− mouse shows several abnormalities, such as a decrease in neuronal density in the cortex and a reduction of 50% in the

SOCS2 and cancer

There are very few reports relating SOCS2 with cancer, in contrast to what is found for other members of the family such as SOCS1. Hypermethylation of the SOCS1 promoter and silencing of the gene have been detected in several cancers, suggesting SOCS1 as a tumor suppressor gene [65]. SOCS2 has been associated with myeloid leukemia, pulmonary adenocarcinoma, and ovarian, breast, and anal cancers. SOCS2 expression is constitutive in normal peripheral blood mononuclear leukocytes (PBMC) and

General conclusions

Since the first description of the SOCS proteins less than a decade ago, there has been considerable progress in the understanding of the role of SOCS proteins in health and disease (see Fig. 2). Given the gigantism observed in SOCS2-deficient mice, most studies until now have focused in the regulation of the GH receptor signaling by SOCS2, until now. Nevertheless, it is now evident that not only GH receptor, but the IGF-1 receptor and other cytokine receptors may be targets of SOCS2 actions,

Acknowledgements

The authors’ studies described in this review were funded by Grants to A.F-M from the Swedish Research Council, Wallenberg Foundation and the Swedish Institute. L.F-P was supported by the Ministerio de Sanidad y Consumo (FIS 1/1000) and Ministerio de Educación y Ciencia (PETRI1995-0711 and SAF2003-02117). We apologize to those whose work is relevant to this topic but was not cited and discussed due to limitations of space.

Elizabeth Rico-Bautista was born on 11 November 1973, Chemist from the National University of Colombia, Bogotá, Colombia (1996) with a master in biochemistry (1999) from the same university and a PhD in cell biology from the Karolinska Institute, Stockholm, Sweden (2005). During her undergraduate and master studies, she mainly focused on the GH-IGFI axis in rat while the doctorate work was based on the action of SOCS2 as a negative regulator of the growth hormone signaling pathway. The latest

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    Elizabeth Rico-Bautista was born on 11 November 1973, Chemist from the National University of Colombia, Bogotá, Colombia (1996) with a master in biochemistry (1999) from the same university and a PhD in cell biology from the Karolinska Institute, Stockholm, Sweden (2005). During her undergraduate and master studies, she mainly focused on the GH-IGFI axis in rat while the doctorate work was based on the action of SOCS2 as a negative regulator of the growth hormone signaling pathway. The latest work that has been published in several international journals. During her PhD studies she was a guest researcher at the Novo Nordiska Laboratories in Copenhagen, Denmark and at the Walter and Eliza Hall Institute (WEHI), Melbourne, Australia. She also started focusing on the ubiquitin–proteasome pathway as a regulator of several cellular processes during her PhD. Currently, she is a post-doctoral fellow at the Department of Genetic and Complex Diseases, Harvard School of Public Health, Harvard University, where she is focusing on the role of the ubiquitin–proteasome pathway in the regulation of cyclin kinase inhibitors.

    Amilcar Flores-Morales obtained his BSc in biochemistry from the University of Havana in 1993 and his PhD in chemistry in 1998 from the National University of Colombia. He is currently an associate professor of experimental endocrinology at the Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden. His research is focused in the understanding of the intracellular mechanisms participating in the regulation hormone actions on target tissues. He has pioneered the use of genomic technologies in endocrinology and is a regular contributor to journals in the field.

    Leandro Fernández-Pérez was born on 5 May 1961, obtained his MD at medical faculty from the University of La Laguna (Spain) in 1985 and his PhD in pharmacology in 1990 at same university. He is currently a professor of pharmacology in medicine and a senior scientist (Molecular Endocrinology Group) at the University of Las Palmas of Gran Canaria (Spain). He has worked as post-doctoral fellowship at Medical Nutrition Department (NOVUM) and Center for Molecular Medicine from Karolinska Institute (Sweden). His research is focused in the understanding of the molecular mechanisms participating in the regulation hormone actions. He has been particularly involved in the elucidation of negative regulatory pathways (SOCS) that control growth hormone signaling. His name is also connected with studies in the field of steroids, in particular to the identification of novel membrane receptors for androgenic–anabolic steroids (stanozolol) and glucocorticoids. Regularly, he is reviewer for international journals with impact factor mainly in the fields of experimental pharmacology and endocrinology.

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