Protein & Cell. Feb/28/2014; 5(3): 203-213

Published online Mar/15/2014

PMID: 24633815

PMC: 3967058

doi: 10.1007/s13238-014-0030-7

Inputs and outputs of insulin receptor

Yipeng Du

Taotao Wei

Abstract

Introduction

Input and output are two basic concepts in the field of cellular signal transduction (Waltermann and Klipp, 2011). In general, the inputs of a signal transduction pathway are the upstream stimulation and inhibition signals, whereas the outputs are the downstream effects, such as the activation of substrates and interactions with other proteins. The classical insulin signaling pathway is initiated by the binding of insulin to the insulin receptor (IR) and the subsequent activation of insulin receptor substrate (IRS) proteins (Taniguchi et al., 2006). For the hub protein IR, the input is insulin, and the output is the phosphorylation of IRS proteins. However, the scenario is not as simple as this one-way signal transduction model. Recent progress in IR signaling indicated that insulin is not the only ligand for IR, and the phosphorylation of IRS proteins represents just one component of IR output. To provide a more complete understanding of the signals mediated through IR, we reviewed the inputs and outputs of IR in this study. We will first provide a brief description of the classical stimulus and substrates of IR and then mainly focus on the factors that positively and negatively regulate IR and the various IR substrates and interacting proteins.

CLASSICAL INPUTS AND OUTPUTS OF IR

The binding of insulin to the α subunits of IR heterotetramer is the main input into the insulin signaling pathway. The IR then undergoes a conformational change in its intracellular β subunits that exposes its ATP-binding domain, which enables ATP binding and autophosphorylation. The output of IR activation is the phosphorylation of a group of IRS proteins (White and Kahn, 1994). IRS1 is the principal IRS protein and is phosphorylated at multiple tyrosine sites upon insulin stimulation (Sun et al., 1993). The tyrosine-phosphorylated IRS1 sites function by docking with SH2 domain-containing proteins and mediating signal transduction to various downstream factors. IRS2 is an alternative IR substrate that was discovered in IRS1-deficient mice (Patti et al., 1995). IRS1 and IRS2 are not functionally redundant, although they both activate many similar downstream pathways (Waters and Pessin, 1996; Hanke and Mann, 2009). IRS3 was first cloned in rat adipocytes and then in mouse. However, this homolog does not appear to exist in human cells (Lavan et al., 1997b; Sciacchitano and Taylor, 1997). IRS4 is the dominant IRS in HEK293 cells (Lavan et al., 1997a). Although IRS1 and IRS2 are present in the HEK293 cell line, they are not activated upon insulin stimulation (Fantin et al., 1998). These results indicate that the output of IR is tissue-specific. IRS5 and IRS6, also known as DOK4 and DOK5, are readily phosphorylated in CHO-IR cells (Cai et al., 2003). IR-phosphorylated IRS5 binds to a number of SH2 domain-containing proteins, that are distinct from those associated with IRS1. However, IR-phosphorylated IRS6 does not bind to any SH2 domain-containing proteins, which indicates that it may mediate a different branch of the insulin signaling pathway (Cai et al., 2003). Shc interacts with and is phosphorylated by IR. Phosphorylated Shc can dock with Grb2 and mediate signal transduction through the Ras-MAPK signaling pathway (Sasaoka and Kobayashi, 2000). Gab1 is another IRS protein that is mainly involved in the PI3K-Akt pathway (Lehr et al., 2000). The p85α subunit of PI3K can be directly phosphorylated by IR after its docking to IRS1/2 (Hayashi et al., 1993; Van Horn et al., 1994). Although the classical IR inputs and outputs are simple and clear, they are only part of the story (Fig. 1A).

Figure 1

The diagram illustrating the inputs and outputs of insulin receptor. (A) Classical IR inputs and outputs. (B) Summary of proteins associating with IR which include positive modulator (purple), negative modulator (red), alternative substrates (green) and interactors (blue). Arrow: stimulation; Line: interaction; Arrow with flathead: inhibition

In addition to the classical IRS proteins, many other proteins have been shown to associate with IR and to play a role in the insulin signaling pathway (Fig. 1B), which could be classified into four different types: (1) Positive modulators of IR (e.g., glypican-4 stimulates insulin function by binding to IR); (2) Negative modulators of IR [e.g., protein tyrosine phosphatases (PTPs), protein kinase C (PKC) isoforms, growth factor receptor-bound (Grb) and suppressors of cytokine signaling (SOCS) proteins]; (3) Alternative IR substrates involved in various biological processes; and (4) proteins that interact with IR, but are not its substrates. The following section will focus on these four types of proteins in an attempt to provide a complete description of the inputs and outputs of IR. The related proteins and references are summarized in Table 1.

Table 1

Proteins associated with the inputs and outputs of insulin receptor

Positive modulatorsNegative modulatorsAlternative substratesProteins interacting with IR, but are not its substrates (Interactors)

Protein	Function	References
Glypican-4	Binds IR α subunits. Facilitates insulin-induced formational change of IR	Ussar et al. 2012
PTP1B	Major PTP involved in insulin signaling. Dephosphorylates IR tyrosine	Salmeen et al. 2000
TCPTP	Cooperates with PTP1B. Dephosphorylate IR tyrosine	Galic et al. 2003
PTPRF	Dephosphorylates IR tyrosine	Hashimoto et al. 1992
PKCδ	Predominant in muscle. Phosphorylates IR serine	Braiman et al. 2001
PKCε	Predominant in liver. Phosphorylates IR serine	Samuel et al. 2007
Grb7	Binds IR in vitro and in vivo	Kasus-Jacobi et al. 2000
Grb10	Binds IR. Blocks IRS1/2	Wick et al. 2003
Grb14	Binds IR. Blocks PTP1B	Nouaille et al. 2006
SOCS1	Binds IR. Interrupts IRS2	Ueki et al. 2004
SOCS3	Binds IR. Interrupts IRS1/2, STAT5B	Emanuelli et al. 2000
SOCS6	Binds IR. Interrupts IRS1	Mooney et al. 2001
ENPP1	Binds IR α subunits. Inhibits insulin-induced conformational change of IR	Maddux and Goldfine, 2000
AHSG	Binds IR β subunits extracellular region	Mathews et al. 2000
ADRB2	Transmembrane protein. Phosphorylated by IR in vitro and in vivo	Baltensperger et al. 1996
Calmodulin	Calcium-dependent protein. Phosphorylated by IR in vitro and in vivo	Sacks et al. 1992
CEACAM1	Transmembrane protein. Phosphorylated by IR in vitro and in vivo	Poy et al. 2002a
Dok1	GAP-associated protein. Phosphorylated by IR in vitro and in vivo	Wick et al. 2001
FABP4	Fatty acid-binding protein. Phosphorylated by IR in vitro	Buelt et al. 1991
FAK1	Integrin signaling pathway. Phosphorylated by IR in vitro	Baron et al. 1998
FRS2	FGFR substrate. Phosphorylated by IR in vitro	Delahaye et al. 2000
PTP1C	Protein tyrosine phosphatase. Phosphorylated by IR in vitro and in vivo	Uchida et al. 1994
SH2B1	Interacts with IR and phosphorylated upon insulin stimulation in vivo	Kotani et al. 1998
SH2B2	Interacts with IR and phosphorylated upon insulin stimulation in vivo	Moodie et al. 1999
STAT5B	Transcriptional factor. Phosphorylated by IR in vitro and in vivo	Chen et al. 1997
SYNCRIP	RNA-binding protein. Phosphorylated by IR in vitro	Hresko and Mueckler, 2002
Sam68	RNA-binding protein. Phosphorylated by IR in vitro and in vivo	Sanchez-Margalet and Najib, 1999
Vav3	Interacts with and phosphorylated by IR activation in vivo	Zeng et al. 2000
ARF	Interacts with activated IR. PLD regulation	Shome et al. 1997
hMAD2	Interacts with inactivated IR	O’Neill et al. 1997
JAK1	Interacts with activated IR. Enhances IRS1 activation	Gual et al. 1998
PLCγ1	Interacts with activated IR. Enhances MAPK activation	Kwon et al. 2003
PTP1D	Interacts with activated IR. Enhances IRS1 activation	Kharitonenkov et al. 1995
RACK1	Interacts with activated IR. Facilitates STAT3 activation	Zhang et al. 2006
SORBS1	Interacts with inactivated IR	Lin et al. 2001

POSITIVE MODULATORS OF IR

Insulin, IGF1 and IGF2 are traditional IR ligands. Some adipokines have also been found to interact with the IR α subunits and to enhance insulin sensitivity. Glypican-4, which is released from adipose tissue into the circulation, is a potential IR ligand. It binds to IR at regions different from that of insulin (Ussar et al., 2012). The depletion of glypican-4 reduces insulin signaling, whereas the overexpression of wild-type glypican-4 enhances the insulin-mediated phosphorylation of ERK and AKT (Ussar et al., 2012), indicating its potential role as a target for the treatment of insulin resistance (Mitchell, 2012). Visfatin is related to the insulin signaling pathway, but its role in the stimulation of IR remains controversial (Adeghate, 2008).

NEGATIVE MODULATORS OF IR

The activity of IR is negatively regulated by several mechanisms. PTPs can dephosphorylate IR at autophosphorylated tyrosines and thus inactivate IR. Members of the PKC family phosphorylate serines near autophosphorylated tyrosine sites to disrupt the docking of SH2 domain-containing proteins. Proteins in the Grb and SCOS families bind directly to IR and block its interaction with downstream factors. In addition, other proteins, such as NEPP1 and AHSG, inhibit IR by interacting with its extracellular domain. This indicates that a variety of negative modulators of IR cooperate to inactivate IR. We here summarized the important negative modulators of IR.

PTPs (PTP1B, PTP1C, TCPTP and PTPRF)

PTPs are encoded by approximately 100 genes in humans (Alonso et al., 2004; Tonks, 2006). Classical PTPs dephosphorylate tyrosine phosphorylation to attenuate the function of many receptor tyrosine kinases (Andersen et al., 2001; Andersen et al., 2004). At least three PTPs proteins have been found to be involved in the negative regulation of IR by dephosphorylation. PTP1B is the best-known and most-studied PTP and regulates IR activity via dephosphorylation. It can be recruited to multiply tyrosine phosphorylation sites on the IR through its SH2 domain upon insulin stimulation and IR autophosphorylation (Seely et al., 1996). The tyrosines of PTP1B are then phosphorylated by IR, and this step greatly increases its dephosphorylation activity (Dadke et al., 2001). Phosphorylated PTP1B can dephosphorylate IR and inhibit its kinase activity (Salmeen et al., 2000). This typical negative feedback is widely present in biological processes. In addition, phosphorylated PTP1B can dephosphorylate itself to balance its catalytic activity. PTP1B has been recognized as a potential target for the enhancement of insulin sensitization through a series of functional studies (Delibegovic et al., 2007; Picardi et al., 2008; Delibegovic et al., 2009; Ma et al., 2011). Similar to PTP1B, TCPTP uses autophosphorylated IR as a direct substrate both in vivo and in vitro (Lammers et al., 1993; Galic et al., 2003). Although both PTP1B and TCPTP inhibit the activity of IR by dephosphorylation, the catalytic tyrosine sites might be different. PTP1B prefers to tandem phosphorylate tyrosine, whereas TCPTP mainly catalyzes a single phosphorylated tyrosine (Galic et al., 2005). PTPRF, which is a transmembrane PTP, also interacts with and dephosphorylates IR in vitro and in vivo (Hashimoto et al., 1992; Ahmad and Goldstein, 1997). It can be deduced that PTP1B, TCPTP and PTPRF crosstalk with each other to negatively regulate IR. In summary, three PTPs can act as negative inputs to IR via tyrosine dephosphorylation under conditions of insulin stimulation.

PKCs (PKCδ and PKCε)

The PKC family consists of three distinct groups, namely, the classical, novel and atypical groups. In contrast to PTPs, which dephosphorylate proteins, PKCs function by phosphorylating serines or threonines. Several members in the PKC family have been shown to be involved in negatively regulating IR activity. In vitro-purified PKC can also phosphorylate IR and lower its tyrosine kinase activity (Bollag et al., 1986). In vivo studies using insulin-resistant human skeletal muscle suggest that PKCδ is recruited to IR and reduces its activity via serine phosphorylation (Itani et al., 2000; Braiman et al., 2001; Rosenzweig et al., 2004). In insulin-resistant liver, PKCε is the predominant activated PKC. PKCε inhibits insulin signaling by binding to IR and reducing its tyrosine kinase activity in hepatic steatosis (Samuel et al., 2007; Jornayvaz et al., 2011; Jornayvaz and Shulman, 2012). These studies indicate that PKC isoforms regulate IR activity in a tissue-specific manner. In addition, PKC can inhibit the insulin signaling pathway by phosphorylating other proteins in the insulin signaling pathway. For example, PKCθ prefers IRS1 for phosphorylation (Griffin et al., 1999; Yu et al., 2002; Li et al., 2004). In summary, at least two PKCs act as negative inputs to IR via serine phosphorylation.

Grb proteins (Grb10, Grb14 and Grb7)

Unlike PTPs and PKC, which inhibit IR by covalently modification, Grb proteins reduce the activity of IR through direct interaction. The autophosphorylated tyrosine sites on IR not only dock IRS but also SH2 domain-containing proteins, which are not phosphorylated or activated by IR. These types of proteins compete with IRS for IR binding and then serve to inhibit IR activity. Grb10 was first found to be a high affinity interacting protein with IR in vitro (Liu and Roth, 1995). Further studies demonstrated that the Grb10 SH-2 domain and IR carboxyl catalytic active loop are required for this interaction (Hansen et al., 1996). Grb10 binds to the same domain as IRS1 on IR. This binding blocks the IR-mediated phosphorylation of IRS1 and disrupts the IRS1-PI3K signaling pathway (Wick et al., 2003). The biological role of Grb10 in promoting insulin signaling has been proven using a mouse model (Smith et al., 2007; Wang et al., 2007). Similar to Grb10, Grb14 binds to IR and blocks its autophosphorylation in a site-specific manner (Nouaille et al., 2006). The phenotypes of mice deficient in Grb14 and Grb10 differ, which indicates the non-redundant functions of these two proteins (Holt and Siddle, 2005). Grb7 is an additional Grb protein that participates in IR regulation. It binds to activated IR both in vitro and in vivo and may function in the same manner as Grb14 and Grb10 (Kasus-Jacobi et al., 2000). In summary, three Grb proteins can inhibit IR activity by directly blocking downstream signaling.

SOCS proteins (SOCS1, SOCS3 and SOCS6)

Initially identified as cytokine signaling inhibitors, SOCS proteins participate in various signal transduction pathways, including the insulin signaling pathway. Similar to Grb proteins, SOCS proteins directly interact with IR and block downstream signal transduction. For example, SOCS3 attenuates the IR-STAT5B signal branch by competing with STAT5B for binding to IR at phosphorylated tyrosine 960 (Emanuelli et al., 2000). SOCS3 also interrupts the IRS1 and IRS2 signal branch with the same mechanism (Ueki et al., 2004). Moreover, SOCS3 overexpression in cultured cells inhibits IR autophosphorylation. This mechanism is most likely mediated by crosstalk between IR regulators (Senn et al., 2003). In addition, SOCS3 is induced by STAT5B upon insulin stimulation (Emanuelli et al., 2000; Sadowski et al., 2001). This constitutes another negative feedback loop in the insulin signaling pathway. SOCS1 binds to IR on sites different from that of SOCS3, although they are both IR inhibitors (Mooney et al., 2001; Le et al., 2002; Ueki et al., 2004). SOCS6 binds to both IR and IRS4, which indicates that it inhibits the insulin signaling pathway by targeting multiple proteins (Mooney et al., 2001; Krebs et al., 2002). SOCS proteins can be induced by inflammation, which partially explains the role of inflammation in insulin resistance (Tanti et al., 2012; Suchy et al., 2013). We concluded that at least three SOCS proteins provide negative inputs to IR.

ENPP1

ENPP1 (ectonucleotide pyrophosphatase/phosphodiesterase family member 1) is a transmembrane protein with alkaline phosphodiesterase and nucleotide pyrophosphatase activity. However, its inhibition of IR autophosphorylation is independent of its enzymatic activity (Grupe et al., 1995). In contrast to Grb and SOCS proteins, which inhibit IR activity by interacting with its β subunits, ENPP1 directly binds to the IR α subunits (Maddux and Goldfine, 2000). ENPP1 does not appear to affect insulin binding, but inhibits the insulin-induced conformational change of the IR α subunits (Maddux and Goldfine, 2000). The ENPP1 K173Q polymorphism (previously described as K121Q) has been associated with insulin resistance (Costanzo et al., 2001; McAteer et al., 2008; Moore et al., 2009) because the K173Q polymorphism tightly binds to IR and effectively inhibits IR. There are seven members in the ENPP family (Masse et al., 2010). Given the similarity between ENPP1 and the other ENPPs, particularly ENPP2 (Kato et al., 2012), it is possible that these other ENPPs may participate in the insulin signaling pathway. Furthermore, the up-regulation of ENPP2 has been associated with insulin resistance in a diabetic mouse model (Boucher et al., 2005). Thus, it can be concluded that ENPP1 inhibits IR by blocking the conformational change of IR upon insulin binding.

AHSG

AHSG (alpha-2-Heremans-Schmid glycoprotein) inhibits the autophosphorylation of IR by interacting with the extracellular region of its β subunits (Auberger et al., 1989; Srinivas et al., 1993; Mathews et al., 2000). The mechanism of this inhibition may be similar to that of ENPP1. AHSG is secreted by the liver and is released into the circulation. The blood levels of AHSG have been correlated with insulin resistance (Kalabay et al., 2002; Goustin and Abou-Samra, 2011). Thus, it is becoming clear that AHSG is another negative input of IR.

ALTERNATIVE SUBSTRATES OF IR

IR substrates are not restricted to the classical ones mentioned above. A variety of proteins have been found to be phosphorylated by activated IR. We categorized these proteins into different IR outputs and review their roles in the insulin signaling pathway in this section.

ADRB2

ADRB2 (beta-2-adrenergic receptor) is a member of the G-protein coupled receptor superfamily and can be phosphorylated by IR both in vivo and in vitro (Baltensperger et al., 1996). The phosphorylated tyrosine site on ADRB2 can recruit Grb2 and other proteins to promote the internalization of ADRB2 (Karoor et al., 1998). This indicates that the insulin signaling pathway may crosstalk with the GPCR (G-protein coupled receptor) signaling pathway.

Calmodulin

Calmodulin is a multifunctional calcium-dependent messenger protein that can be phosphorylated by different types of kinases, including IR (Laurino et al., 1988; Sacks and McDonald, 1988; Wong et al., 1988; Sacks et al., 1989; Sacks and McDonald, 1989; Sacks et al., 1992). The phosphorylation of calmodulin has an effect on its intrinsic enzyme property and on its downstream interacting proteins (Benaim and Villalobo, 2002). IR phosphorylates calmodulin at two major tyrosine sites, which attenuates its biological activity (Saville and Houslay, 1994; Williams et al., 1994; Sacks et al., 1995; Joyal et al., 1996). However, the precise role of this phosphorylation related to insulin signaling is unclear. Calmodulin may serve as a node for the crosstalk between the insulin signaling pathway and other signaling pathways.

CEACAM1

CEACAM1 (carcinoembryonic antigen-related cell adhesion molecule 1) is another transmembrane substrate of IR. IR phosphorylates CEACAM1 on its intracellular domain to initiate IR internalization (Formisano et al., 1995). CEACAM1-mediated IR internalization and degradation is important for insulin clearance in the liver (Poy et al., 2002b). The tyrosine-phosphorylated sites on CEACAM1 also compete with IR for Shc binding, thus attenuating IR signaling transduction to the MARK pathway (Poy et al., 2002a).

Dok1

Dok1 (docking protein 1) is phosphorylated by IR at specific tyrosine sites. Phosphorylated Dok1 enhances its binding to GAP, which is an inhibitor of RAS (Wick et al., 2001). Thus, RAS is dually regulated by the insulin signaling pathway: it is activated by Grb2-SOS and inactivated by Dok1-GAP. Dok2 and Dok3 do not appear to be related to the insulin signaling pathway, but these proteins interact with GAP and may play an important role in other pathways (Di Cristofano et al., 1998; Lemay et al., 2000).

FABP4

FABP4 (fatty acid-binding protein 4) is mainly expressed in adipocytes, which can be phosphorylated by the purified IR β subunits in vitro (Buelt et al., 1991). In addition, results obtained from FABP4-deficient mice indicate that this protein may serve as a bridge linking obesity to insulin resistance (Hotamisligil et al., 1996). However, it remains unclear whether FABP4 is a substrate of IR in vivo and whether it participates in the insulin signaling pathway.

FAK1

FAK1 (focal adhesion kinase 1) is a cytosolic tyrosine kinase involved in integrin signaling. IR promotes FAK1 phosphorylation in suspended cells (Baron et al., 1998). In contrast, IR stimulates the dephosphorylation of FAK1 in attached cells (Pillay et al., 1995). The biological role of IR-phosphorylated FAK1 remains to be elucidated. The dual role of IR in FAK1 regulation may be related to the integrin-mediated signaling pathway.

FRS2

FRS2 (fibroblast growth factor receptor substrate 2) was originally found to be an adapter protein that links activated FGR receptors to the downstream signaling pathway (Xu et al., 1998). It has also been revealed to be a direct substrate of IR in vitro and becomes tyrosine phosphorylated upon insulin stimulation in vivo (Delahaye et al., 2000).

PTP1C

PTP1C is able to bind to autophosphorylated IR and is phosphorylated by activated IR on its tyrosine residues (Uchida et al., 1994). In addition, the phosphatase activity of phosphorylated PTP1C increases. However, there is no evidence demonstrating that it can directly dephosphorylate IR, although PTP1C-deficient mice exhibit increased glucose tolerance and insulin sensitivity (Dubois et al., 2006).

SH2B1/2

SH2B1 and 2 are SH2 domain-containing proteins that can be tyrosine phosphorylated upon insulin stimulation (Yokouchi et al., 1997; Kotani et al., 1998; Wang and Riedel, 1998; Moodie et al., 1999). The insulin-induced phosphorylation of SH2B1/2 is potentially mediated by IR. Similar to Grb2 and Shc, phosphorylated SH2B1 and 2 may serve as a docking site for downstream factors. For example, phosphorylated SH2B2 can dock c-Cbl to IR and promote IR ubiquitination and internalization (Ahmed et al., 2000). In addition, SH2B 1 and 2 serve as an adaptor and substrates for other tyrosine kinase receptors, such as receptors of PDGF (platelet-derived growth factor), NGF (nerve growth factor), and FGF (fibroblast growth factor) (Rui and Carter-Su, 1998; Kong et al., 2002; Wang et al., 2004).

STAT5B

STAT5B (signal transducer and activator of transcription 5B) has been demonstrated to be a direct substrate for IR both in vitro and in vivo (Chen et al., 1997; Sawka-Verhelle et al., 1997; Storz et al., 1999; Sawka-Verhelle et al., 2000). Phosphorylated STAT5B acts as a transcription factor and activates a series of target genes, including glucokinase and SOCS proteins (Sawka-Verhelle et al., 2000; Sadowski et al., 2001). Insulin-induced gene expression events may be partially mediated by STAT5B.

SYNCRIP and Sam68

IR substrates are not restricted to cytoplasmic enzymes and transcriptional factors. IR also phosphorylates RNA-binding proteins. For instance, the RNA-binding protein SYNCRIP (synaptotagmin-binding cytoplasmic RNA-interacting protein) is phosphorylated by IR in vitro (Hresko and Mueckler, 2000, 2002). Moreover, this phosphorylation can be disrupted by RNA binding. The RNA-binding protein Sam68, which can be induced by insulin, is phosphorylated by IR both in vitro and in vivo (Sanchez-Margalet and Najib, 1999; Sanchez-Margalet et al., 2003). Tyrosine-phosphorylated Sam68 (the 68 kDa Src substrate associated during mitosis) can dock with p85 PI3K and GAP proteins (Sanchez-Margalet and Najib, 2001). The RNA-binding activity of Sam68 is also affected by tyrosine phosphorylation (Wang et al., 1995), indicating a role of the insulin signaling pathway in RNA metabolism.

Vav3

Vav3 is a member of the guanine nucleotide exchange factor family, which activates multiple pathways. Vav3 interacts with and is phosphorylated by IR when overexpressed in 293T cells (Zeng et al., 2000). IR-phosphorylated Vav3 promotes Rac-1 activation and actin cytoskeletal rearrangement and modulates the formation of cell membrane ruffles (Zeng et al., 2000).

PROTEINS INTERACT WITH IR BUT ARE NOT ITS SUBSTRATES

IR does not always provide an output signal via catalysis. Under certain conditions, signals from IR are transmitted by changes in its interaction status with its binding partners. For example, inactivated IR interacts with hMAD2 (human homolog of yeast MAD2) with high affinity. This interaction decreases upon IR activation (O’Neill et al., 1997). Similarly, SORBS1 (sorbin and SH3 domain-containing 1) dissociates from IR and binds to c-Abl upon insulin stimulation (Lin et al., 2001). Although the biological function of these types of proteins in the insulin signaling pathway remains unclear, they enable signal transduction through IR.

In cells overexpressing IR, JAK1 (Janus kinase 1) has been observed to interact with IR (Gual et al., 1998). In addition, the phosphorylation of both proteins is necessary for their interaction. The binding of JAK1 to IR may facilitate its catalytic activity to IRS1. RACK1 (receptor for activated C kinase 1) interacts with both IR and STAT3 in vitro. In addition, RACK1 mediates IR-induced STAT3 activation in vivo (Zhang et al., 2006). These results indicate that IR transmits signals to STAT3 via RACK1. ARF (ADP-ribosylation factor) has been coimmunoprecipitated with activated IR and serves as an adaptor to IR-mediated PLD regulation (Shome et al., 1997). In addition, PTP1D (protein tyrosine phosphatase 1D), which is a member of the PTP family, can bind to both IR and IRS1 and enhance the docking of IRS1 to IR (Kharitonenkov et al., 1995). PLCγ1 (phospholipase C gamma 1) can interact with activated IR in a SH2 domain-independent manner, which may be mediated by conformational changes of IR (Kwon et al., 2003). The binding to PLCγ1 leads to phosphorylation, which plays a role in signal transduction to MAPK. Thus, the IR-mediated signals can be transmitted by interacting proteins independent of its catalytic activity.

Conclusions

After four decades of extensive investigation, a growing body of knowledge on IR has been accumulated. In this review, we summarized the signals input to or output from IR (Fig. 1). Although each signal branch through IR is clear and understandable, the integration of all of the signal branches to obtain a full understanding of insulin signaling remains challenging. To fully understand the IR signaling cascades, it is not sufficient to study IR-interacting proteins or signal branches one-by-one; all related proteins and pathways must be integrated. The typical cellular response to insulin stimulation is the phosphorylation of classical IRS and IRS-mediated macromolecular complex docking. However, we should consider other independently reported docking proteins, such as Dok1, SH2B1 and SH2B2 to the macromolecular docking process. In parallel with the docking event is the direct activation of a group of proteins, including calmodulin, STAT5B and SYNCRIP. We should also integrate the negative regulation mechanisms with the activation event triggered by IR. The represented members of negative regulators are PTPs, PKCs, Grb and SOCS proteins. In addition, insulin may be dissociated or internalized and degraded via a CEACAM-mediated mechanism. Add there should be other IR related proteins and events which remain to be elucidated. Only if the input and output signals are integrated into one story, we may eventually obtain a full understanding of IR signaling.

Acknowledgments

This work was supported by grants from the National Basic Research Program of China (2010CB833701) and the National Natural Science Foundation of China (Grant No. 31070736). The authors are indebted to Profs. Fuyu Yang and Pingsheng Liu (IBP, CAS) for helpful comments and suggestions.

COMPLIANCE WITH ETHICS GUIDELINES

Yipeng Du and Taotao Wei declare that they have no conflict of interest.

This article does not contain any studies with human or animal subjects performed by the any of the authors.

Abbreviations

CEACAM1carcinoembryonic antigen-related cell adhesion molecule 1

Dok1docking protein 1

FABP4fatty acid-binding protein 4

FRS2fibroblast growth factor receptor substrate 2

Grbgrowth factor receptor-bound

IRinsulin receptor

IRSinsulin receptor substrate

JAK1Janus kinase 1

PKCprotein kinase C

PTPprotein tyrosine phosphatase

RACK1receptor for activated C kinase 1

Sam68the 68 kDa Src substrate associated during mitosis

SOCSsuppressors of cytokine signaling

SORBS1sorbin and SH3 domain-containing 1

STAT5Bsignal transducer and activator of transcription 5B

SYNCRIPsynaptotagmin-binding cytoplasmic RNA-interacting protein

References

1. AdeghateEVisfatin: structure, function and relation to diabetes mellitus and other dysfunctionsCurr Med Chem20081518511862[PubMed][Google Scholar]
2. AhmadFGoldsteinBJFunctional association between the insulin receptor and the transmembrane protein-tyrosine phosphatase LAR in intact cellsJ Biol Chem1997272448457[PubMed][Google Scholar]
3. AhmedZSmithBJPillayTSThe APS adapter protein couples the insulin receptor to the phosphorylation of c-Cbl and facilitates ligand-stimulated ubiquitination of the insulin receptorFEBS Lett20004753134[PubMed][Google Scholar]
4. AlonsoASasinJBottiniNFriedbergIFriedbergIOstermanAGodzikAHunterTDixonJMustelinTProtein tyrosine phosphatases in the human genomeCell2004117699711[PubMed][Google Scholar]
5. AndersenJNMortensenOHPetersGHDrakePGIversenLFOlsenOHJansenPGAndersenHSTonksNKMollerNPStructural and evolutionary relationships among protein tyrosine phosphatase domainsMol Cell Biol20012171177136[PubMed][Google Scholar]
6. AndersenJNJansenPGEchwaldSMMortensenOHFukadaTDel VecchioRTonksNKMollerNPA genomic perspective on protein tyrosine phosphatases: gene structure, pseudogenes, and genetic disease linkageFASEB J200418830[PubMed][Google Scholar]
7. AubergerPFalquerhoLContreresJOPagesGLe CamGRossiBLe CamACharacterization of a natural inhibitor of the insulin receptor tyrosine kinase: cDNA cloning, purification, and anti-mitogenic activityCell198958631640[PubMed][Google Scholar]
8. BaltenspergerKKaroorVPaulHRuohoACzechMPMalbonCCThe beta-adrenergic receptor is a substrate for the insulin receptor tyrosine kinaseJ Biol Chem199627110611064[PubMed][Google Scholar]
9. BaronVCallejaVFerrariPAlengrinFVan ObberghenEp125Fak focal adhesion kinase is a substrate for the insulin and insulin-like growth factor-I tyrosine kinase receptorsJ Biol Chem199827371627168[PubMed][Google Scholar]
10. BenaimGVillaloboAPhosphorylation of calmodulin. Functional implicationsEur J Biochem200226936193631[PubMed][Google Scholar]
11. BollagGERothRABeaudoinJMochly-RosenDKoshlandDEJrProtein kinase C directly phosphorylates the insulin receptor in vitro and reduces its protein-tyrosine kinase activityProc Natl Acad Sci USA19868358225824[PubMed][Google Scholar]
12. BoucherJQuilliotDPraderesJPSimonMFGresSGuigneCPrevotDFerryGBoutinJACarpeneCPotential involvement of adipocyte insulin resistance in obesity-associated up-regulation of adipocyte lysophospholipase D/autotaxin expressionDiabetologia200548569577[PubMed][Google Scholar]
13. BraimanLAltAKurokiTOhbaMBakATennenbaumTSampsonSRInsulin induces specific interaction between insulin receptor and protein kinase C delta in primary cultured skeletal muscleMol Endocrinol200115565574[PubMed][Google Scholar]
14. BueltMKShekelsLLJarvisBWBernlohrDAIn vitro phosphorylation of the adipocyte lipid-binding protein (p15) by the insulin receptor. Effects of fatty acid on receptor kinase and substrate phosphorylationJ Biol Chem19912661226612271[PubMed][Google Scholar]
15. CaiDDhe-PaganonSMelendezPALeeJShoelsonSETwo new substrates in insulin signaling, IRS5/DOK4 and IRS6/DOK5J Biol Chem20032782532325330[PubMed][Google Scholar]
16. ChenJSadowskiHBKohanskiRAWangLHStat5 is a physiological substrate of the insulin receptorProc Natl Acad Sci USA19979422952300[PubMed][Google Scholar]
17. CostanzoBVTrischittaVDi PaolaRSpampinatoDPizzutiAVigneriRFrittittaLThe Q allele variant (GLN121) of membrane glycoprotein PC-1 interacts with the insulin receptor and inhibits insulin signaling more effectively than the common K allele variant (LYS121)Diabetes200150831836[PubMed][Google Scholar]
18. DadkeSKusariAKusariJPhosphorylation and activation of protein tyrosine phosphatase (PTP) 1B by insulin receptorMol Cell Biochem2001221147154[PubMed][Google Scholar]
19. DelahayeLRocchiSVan ObberghenEPotential involvement of FRS2 in insulin signalingEndocrinology2000141621628[PubMed][Google Scholar]
20. DelibegovicMBenceKKModyNHongEGKoHJKimJKKahnBBNeelBGImproved glucose homeostasis in mice with muscle-specific deletion of protein-tyrosine phosphatase 1BMol Cell Biol20072777277734[PubMed][Google Scholar]
21. DelibegovicMZimmerDKauffmanCRakKHongEGChoYRKimJKKahnBBNeelBGBenceKKLiver-specific deletion of protein-tyrosine phosphatase 1B (PTP1B) improves metabolic syndrome and attenuates diet-induced endoplasmic reticulum stressDiabetes200958590599[PubMed][Google Scholar]
22. Di CristofanoACarpinoNDunantNFriedlandGKobayashiRStrifeAWisniewskiDClarksonBPandolfiPPReshMDMolecular cloning and characterization of p56dok-2 defines a new family of RasGAP-binding proteinsJ Biol Chem199827348274830[PubMed][Google Scholar]
23. DuboisMJBergeronSKimHJDombrowskiLPerreaultMFournesBFaureROlivierMBeaucheminNShulmanGIThe SHP-1 protein tyrosine phosphatase negatively modulates glucose homeostasisNat Med200612549556[PubMed][Google Scholar]
24. EmanuelliBPeraldiPFillouxCSawka-VerhelleDHiltonDVan ObberghenESOCS-3 is an insulin-induced negative regulator of insulin signalingJ Biol Chem20002751598515991[PubMed][Google Scholar]
25. FantinVRSparlingJDSlotJWKellerSRLienhardGELavanBECharacterization of insulin receptor substrate 4 in human embryonic kidney 293 cellsJ Biol Chem19982731072610732[PubMed][Google Scholar]
26. FormisanoPNajjarSMGrossCNPhilippeNOrienteFKern-BuellCLAcciliDGordenPReceptor-mediated internalization of insulin. Potential role of pp120/HA4, a substrate of the insulin receptor kinaseJ Biol Chem19952702407324077[PubMed][Google Scholar]
27. GalicSKlingler-HoffmannMFodero-TavolettiMTPuryerMAMengTCTonksNKTiganisTRegulation of insulin receptor signaling by the protein tyrosine phosphatase TCPTPMol Cell Biol20032320962108[PubMed][Google Scholar]
28. GalicSHauserCKahnBBHajFGNeelBGTonksNKTiganisTCoordinated regulation of insulin signaling by the protein tyrosine phosphatases PTP1B and TCPTPMol Cell Biol200525819829[PubMed][Google Scholar]
29. GoustinASAbou-SamraABThe “thrifty” gene encoding Ahsg/Fetuin-A meets the insulin receptor: Insights into the mechanism of insulin resistanceCell Signal201123980990[PubMed][Google Scholar]
30. GriffinMEMarcucciMJClineGWBellKBarucciNLeeDGoodyearLJKraegenEWWhiteMFShulmanGIFree fatty acid-induced insulin resistance is associated with activation of protein kinase C theta and alterations in the insulin signaling cascadeDiabetes19994812701274[PubMed][Google Scholar]
31. GrupeAAllemanJGoldfineIDSadickMStewartTAInhibition of insulin receptor phosphorylation by PC-1 is not mediated by the hydrolysis of adenosine triphosphate or the generation of adenosineJ Biol Chem19952702208522088[PubMed][Google Scholar]
32. GualPBaronVLequoyVVan ObberghenEInteraction of Janus kinases JAK-1 and JAK-2 with the insulin receptor and the insulin-like growth factor-1 receptorEndocrinology1998139884893[PubMed][Google Scholar]
33. HankeSMannMThe phosphotyrosine interactome of the insulin receptor family and its substrates IRS-1 and IRS-2Mol Cell Proteomics20098519534[PubMed][Google Scholar]
34. HansenHSvenssonUZhuJLaviolaLGiorginoFWolfGSmithRJRiedelHInteraction between the Grb10 SH2 domain and the insulin receptor carboxyl terminusJ Biol Chem199627188828886[PubMed][Google Scholar]
35. HashimotoNFeenerEPZhangWRGoldsteinBJInsulin receptor protein-tyrosine phosphatases. Leukocyte common antigen-related phosphatase rapidly deactivates the insulin receptor kinase by preferential dephosphorylation of the receptor regulatory domainJ Biol Chem19922671381113814[PubMed][Google Scholar]
36. HayashiHNishiokaYKamoharaSKanaiFIshiiKFukuiYShibasakiFTakenawaTKidoHKatsunumaNThe alpha-type 85-kDa subunit of phosphatidylinositol 3-kinase is phosphorylated at tyrosines 368, 580, and 607 by the insulin receptorJ Biol Chem199326871077117[PubMed][Google Scholar]
37. HoltLJSiddleKGrb10 and Grb14: enigmatic regulators of insulin action–and more?Biochem J2005388393406[PubMed][Google Scholar]
38. HotamisligilGSJohnsonRSDistelRJEllisRPapaioannouVESpiegelmanBMUncoupling of obesity from insulin resistance through a targeted mutation in aP2, the adipocyte fatty acid binding proteinScience199627413771379[PubMed][Google Scholar]
39. HreskoRCMuecklerMA novel 68-kDa adipocyte protein phosphorylated on tyrosine in response to insulin and osmotic shockJ Biol Chem20002751811418120[PubMed][Google Scholar]
40. HreskoRCMuecklerMIdentification of pp68 as the tyrosine-phosphorylated form of SYNCRIP/NSAP1. A cytoplasmic RNA-binding proteinJ Biol Chem20022772523325238[PubMed][Google Scholar]
41. ItaniSIZhouQPoriesWJMacDonaldKGDohmGLInvolvement of protein kinase C in human skeletal muscle insulin resistance and obesityDiabetes20004913531358[PubMed][Google Scholar]
42. JornayvazFRShulmanGIDiacylglycerol activation of protein kinase Cepsilon and hepatic insulin resistanceCell Metab201215574584[PubMed][Google Scholar]
43. JornayvazFRBirkenfeldALJurczakMJKandaSGuigniBAJiangDCZhangDLeeHYSamuelVTShulmanGIHepatic insulin resistance in mice with hepatic overexpression of diacylglycerol acyltransferase 2Proc Natl Acad Sci USA201110857485752[PubMed][Google Scholar]
44. JoyalJLCrimminsDLThomaRSSacksDBIdentification of insulin-stimulated phosphorylation sites on calmodulinBiochemistry19963562676275[PubMed][Google Scholar]
45. KalabayLCsehKPajorABaranyiECsakanyGMMelczerZSpeerGKovacsMSillerGKaradiICorrelation of maternal serum fetuin/alpha2-HS-glycoprotein concentration with maternal insulin resistance and anthropometric parameters of neonates in normal pregnancy and gestational diabetesEur J Endocrinol2002147243248[PubMed][Google Scholar]
46. KaroorVWangLWangHYMalbonCCInsulin stimulates sequestration of beta-adrenergic receptors and enhanced association of beta-adrenergic receptors with Grb2 via tyrosine 350J Biol Chem19982733303533041[PubMed][Google Scholar]
47. Kasus-JacobiABereziatVPerdereauDGirardJBurnolAFEvidence for an interaction between the insulin receptor and Grb7. A role for two of its binding domains, PIR and SH2Oncogene20001920522059[PubMed][Google Scholar]
48. KatoKNishimasuHOkudairaSMiharaEIshitaniRTakagiJAokiJNurekiOCrystal structure of Enpp1, an extracellular glycoprotein involved in bone mineralization and insulin signalingProc Natl Acad Sci USA20121091687616881[PubMed][Google Scholar]
49. KharitonenkovASchnekenburgerJChenZKnyazevPAliSZwickEWhiteMUllrichAAdapter function of protein-tyrosine phosphatase 1D in insulin receptor/insulin receptor substrate-1 interactionJ Biol Chem19952702918929193[PubMed][Google Scholar]
50. KongMWangCSDonoghueDJInteraction of fibroblast growth factor receptor 3 and the adapter protein SH2-B. A role in STAT5 activationJ Biol Chem20022771596215970[PubMed][Google Scholar]
51. KotaniKWildenPPillayTSSH2-Balpha is an insulin-receptor adapter protein and substrate that interacts with the activation loop of the insulin-receptor kinaseBiochem J1998335Pt 1103109[PubMed][Google Scholar]
52. KrebsDLUrenRTMetcalfDRakarSZhangJGStarrRDe SouzaDPHanzinikolasKEylesJConnollyLMSOCS-6 binds to insulin receptor substrate 4, and mice lacking the SOCS-6 gene exhibit mild growth retardationMol Cell Biol20022245674578[PubMed][Google Scholar]
53. KwonYKJangHJKoleSHeHJBernierMRole of the pleckstrin homology domain of PLCgamma1 in its interaction with the insulin receptorJ Cell Biol2003163375384[PubMed][Google Scholar]
54. LammersRBossenmaierBCoolDETonksNKSchlessingerJFischerEHUllrichADifferential activities of protein tyrosine phosphatases in intact cellsJ Biol Chem19932682245622462[PubMed][Google Scholar]
55. LaurinoJPColcaJRPearsonJDDeWaldDBMcDonaldJMThe in vitro phosphorylation of calmodulin by the insulin receptor tyrosine kinaseArch Biochem Biophys1988265821[PubMed][Google Scholar]
56. LavanBEFantinVRChangETLaneWSKellerSRLienhardGEA novel 160-kDa phosphotyrosine protein in insulin-treated embryonic kidney cells is a new member of the insulin receptor substrate familyJ Biol Chem19972722140321407[PubMed][Google Scholar]
57. LavanBELaneWSLienhardGEThe 60-kDa phosphotyrosine protein in insulin-treated adipocytes is a new member of the insulin receptor substrate familyJ Biol Chem19972721143911443[PubMed][Google Scholar]
58. LeMNKohanskiRAWangLHSadowskiHBDual mechanism of signal transducer and activator of transcription 5 activation by the insulin receptorMol Endocrinol20021627642779[PubMed][Google Scholar]
59. LehrSKotzkaJHerknerASikmannAMeyerHEKroneWMuller-WielandDIdentification of major tyrosine phosphorylation sites in the human insulin receptor substrate Gab-1 by insulin receptor kinase in vitroBiochemistry2000391089810907[PubMed][Google Scholar]
60. LemaySDavidsonDLatourSVeilletteADok-3, a novel adapter molecule involved in the negative regulation of immunoreceptor signalingMol Cell Biol20002027432754[PubMed][Google Scholar]
61. LiYSoosTJLiXWuJDegennaroMSunXLittmanDRBirnbaumMJPolakiewiczRDProtein kinase C Theta inhibits insulin signaling by phosphorylating IRS1 at Ser(1101)J Biol Chem20042794530445307[PubMed][Google Scholar]
62. LinWHHuangCJLiuMWChangHMChenYJTaiTYChuangLMCloning, mapping, and characterization of the human sorbin and SH3 domain containing 1 (SORBS1) gene: a protein associated with c-Abl during insulin signaling in the hepatoma cell line Hep3BGenomics2001741220[PubMed][Google Scholar]
63. LiuFRothRAGrb-IR: a SH2-domain-containing protein that binds to the insulin receptor and inhibits its functionProc Natl Acad Sci USA1995921028710291[PubMed][Google Scholar]
64. MaYMTaoRYLiuQLiJTianJYZhangXLXiaoZYYeFPTP1B inhibitor improves both insulin resistance and lipid abnormalities in vivo and in vitroMol Cell Biochem20113576572[PubMed][Google Scholar]
65. MadduxBAGoldfineIDMembrane glycoprotein PC-1 inhibition of insulin receptor function occurs via direct interaction with the receptor alpha-subunitDiabetes2000491319[PubMed][Google Scholar]
66. MasseKBhamraSAllsopGDaleNJonesEAEctophosphodiesterase/nucleotide phosphohydrolase (Enpp) nucleotidases: cloning, conservation and developmental restrictionInt J Dev Biol201054181193[PubMed][Google Scholar]
67. MathewsSTChellamNSrinivasPRCintronVJLeonMAGoustinASGrunbergerGAlpha2-HSG, a specific inhibitor of insulin receptor autophosphorylation, interacts with the insulin receptorMol Cell Endocrinol20001648798[PubMed][Google Scholar]
68. McAteerJBPrudenteSBacciSLyonHNHirschhornJNTrischittaVFlorezJCConsortiumEThe ENPP1 K121Q polymorphism is associated with type 2 diabetes in European populations: evidence from an updated meta-analysis in 42, 042 subjectsDiabetes20085711251130[PubMed][Google Scholar]
69. MitchellFObesity: glypican-4: role in insulin signallingNat Rev Endocrinol20128505[PubMed][Google Scholar]
70. MoodieSAAlleman-SposetoJGustafsonTAIdentification of the APS protein as a novel insulin receptor substrateJ Biol Chem19992741118611193[PubMed][Google Scholar]
71. MooneyRASennJCameronSInamdarNBoivinLMShangYFurlanettoRWSuppressors of cytokine signaling-1 and -6 associate with and inhibit the insulin receptor. A potential mechanism for cytokine-mediated insulin resistanceJ Biol Chem20012762588925893[PubMed][Google Scholar]
72. MooreAFJablonskiKAMasonCCMcAteerJBArakakiRFGoldsteinBJKahnSEKitabchiAEHansonRLKnowlerWCThe association of ENPP1 K121Q with diabetes incidence is abolished by lifestyle modification in the diabetes prevention programJ Clin Endocrinol Metab200994449455[PubMed][Google Scholar]
73. NouailleSBlanquartCZilberfarbVBouteNPerdereauDRoixJBurnolAFIssadTInteraction with Grb14 results in site-specific regulation of tyrosine phosphorylation of the insulin receptorEMBO Rep20067512518[PubMed][Google Scholar]
74. O’NeillTJZhuYGustafsonTAInteraction of MAD2 with the carboxyl terminus of the insulin receptor but not with the IGFIR. Evidence for release from the insulin receptor after activationJ Biol Chem19972721003510040[PubMed][Google Scholar]
75. PattiMESunXJBrueningJCArakiELipesMAWhiteMFKahnCR4PS/insulin receptor substrate (IRS)-2 is the alternative substrate of the insulin receptor in IRS-1-deficient miceJ Biol Chem19952702467024673[PubMed][Google Scholar]
76. PicardiPKCalegariVCPradaPOMoraesJCAraujoEMarcondesMCUenoMCarvalheiraJBVellosoLASaadMJReduction of hypothalamic protein tyrosine phosphatase improves insulin and leptin resistance in diet-induced obese ratsEndocrinology200814938703880[PubMed][Google Scholar]
77. PillayTSSasaokaTOlefskyJMInsulin stimulates the tyrosine dephosphorylation of pp125 focal adhesion kinaseJ Biol Chem1995270991994[PubMed][Google Scholar]
78. PoyMNRuchRJFernstromMAOkabayashiYNajjarSMShc and CEACAM1 interact to regulate the mitogenic action of insulinJ Biol Chem200227710761084[PubMed][Google Scholar]
79. PoyMNYangYRezaeiKFernstromMALeeADKidoYEricksonSKNajjarSMCEACAM1 regulates insulin clearance in liverNat Genet200230270276[PubMed][Google Scholar]
80. RosenzweigTAga-MizrachiSBakASampsonSRSrc tyrosine kinase regulates insulin-induced activation of protein kinase C (PKC) delta in skeletal muscleCell Signal20041612991308[PubMed][Google Scholar]
81. RuiLCarter-SuCPlatelet-derived growth factor (PDGF) stimulates the association of SH2-Bbeta with PDGF receptor and phosphorylation of SH2-BbetaJ Biol Chem19982732123921245[PubMed][Google Scholar]
82. SacksDBMcDonaldJMInsulin-stimulated phosphorylation of calmodulin by rat liver insulin receptor preparationsJ Biol Chem198826323772383[PubMed][Google Scholar]
83. SacksDBMcDonaldJMCalmodulin as substrate for insulin-receptor kinase. Phosphorylation by receptors from rat skeletal muscleDiabetes1989388490[PubMed][Google Scholar]
84. SacksDBFujita-YamaguchiYGaleRDMcDonaldJMTyrosine-specific phosphorylation of calmodulin by the insulin receptor kinase purified from human placentaBiochem J1989263803812[PubMed][Google Scholar]
85. SacksDBDavisHWCrimminsDLMcDonaldJMInsulin-stimulated phosphorylation of calmodulinBiochem J1992286Pt 1211216[PubMed][Google Scholar]
86. SacksDBMazusBJoyalJLThe activity of calmodulin is altered by phosphorylation: modulation of calmodulin function by the site of phosphate incorporationBiochem J1995312Pt 1197204[PubMed][Google Scholar]
87. SadowskiCLChoiTSLeMWheelerTTWangLHSadowskiHBInsulin Induction of SOCS-2 and SOCS-3 mRNA expression in C2C12 Skeletal Muscle Cells Is Mediated by Stat5*J Biol Chem20012762070320710[PubMed][Google Scholar]
88. SalmeenAAndersenJNMyersMPTonksNKBarfordDMolecular basis for the dephosphorylation of the activation segment of the insulin receptor by protein tyrosine phosphatase 1BMol Cell2000614011412[PubMed][Google Scholar]
89. SamuelVTLiuZXWangABeddowSAGeislerJGKahnMZhangXMMoniaBPBhanotSShulmanGIInhibition of protein kinase Cepsilon prevents hepatic insulin resistance in nonalcoholic fatty liver diseaseJ Clin Invest2007117739745[PubMed][Google Scholar]
90. Sanchez-MargaletVNajibSp68 Sam is a substrate of the insulin receptor and associates with the SH2 domains of p85 PI3KFEBS Lett1999455307310[PubMed][Google Scholar]
91. Sanchez-MargaletVNajibSSam68 is a docking protein linking GAP and PI3K in insulin receptor signalingMol Cell Endocrinol2001183113121[PubMed][Google Scholar]
92. Sanchez-MargaletVGonzalez-YanesCNajibSFernandez-SantosJMMartin-LacaveIThe expression of Sam68, a protein involved in insulin signal transduction, is enhanced by insulin stimulationCell Mol Life Sci200360751758[PubMed][Google Scholar]
93. SasaokaTKobayashiMThe functional significance of Shc in insulin signaling as a substrate of the insulin receptorEndocr J200047373381[PubMed][Google Scholar]
94. SavilleMKHouslayMDPhosphorylation of calmodulin on Tyr99 selectively attenuates the action of calmodulin antagonists on type-I cyclic nucleotide phosphodiesterase activityBiochem J1994299Pt 3863868[PubMed][Google Scholar]
95. Sawka-VerhelleDFillouxCTartare-DeckertSMotheIVan ObberghenEIdentification of Stat 5B as a substrate of the insulin receptorEur J Biochem1997250411417[PubMed][Google Scholar]
96. Sawka-VerhelleDTartare-DeckertSDecauxJFGirardJVan ObberghenEStat 5B, activated by insulin in a Jak-independent fashion, plays a role in glucokinase gene transcriptionEndocrinology200014119771988[PubMed][Google Scholar]
97. SciacchitanoSTaylorSICloning, tissue expression, and chromosomal localization of the mouse IRS-3 geneEndocrinology199713849314940[PubMed][Google Scholar]
98. SeelyBLStaubsPAReichartDRBerhanuPMilarskiKLSaltielARKusariJOlefskyJMProtein tyrosine phosphatase 1B interacts with the activated insulin receptorDiabetes19964513791385[PubMed][Google Scholar]
99. SennJJKloverPJNowakIAZimmersTAKoniarisLGFurlanettoRWMooneyRASuppressor of cytokine signaling-3 (SOCS-3), a potential mediator of interleukin-6-dependent insulin resistance in hepatocytesJ Biol Chem20032781374013746[PubMed][Google Scholar]
100. ShomeKVasudevanCRomeroGARF proteins mediate insulin-dependent activation of phospholipase DCurr Biol19977387396[PubMed][Google Scholar]
101. SmithFMHoltLJGarfieldASCharalambousMKoumanovFPerryMBazzaniRSheardownSAHegartyBDLyonsRJMice with a disruption of the imprinted Grb10 gene exhibit altered body composition, glucose homeostasis, and insulin signaling during postnatal lifeMol Cell Biol20072758715886[PubMed][Google Scholar]
102. SrinivasPRWagnerASReddyLVDeutschDDLeonMAGoustinASGrunbergerGSerum alpha 2-HS-glycoprotein is an inhibitor of the human insulin receptor at the tyrosine kinase levelMol Endocrinol1993714451455[PubMed][Google Scholar]
103. StorzPDopplerHPfizenmaierKMullerGInsulin selectively activates STAT5b, but not STAT5a, via a JAK2-independent signalling pathway in Kym-1 rhabdomyosarcoma cellsFEBS Lett1999464159163[PubMed][Google Scholar]
104. SuchyDLabuzekKMachnikGKozlowskiMOkopienBSOCS and diabetes–ups and downs of a turbulent relationshipCell Biochem Funct201331181195[PubMed][Google Scholar]
105. SunXJCrimminsDLMyersMGJrMiralpeixMWhiteMFPleiotropic insulin signals are engaged by multisite phosphorylation of IRS-1Mol Cell Biol19931374187428[PubMed][Google Scholar]
106. TaniguchiCMEmanuelliBKahnCRCritical nodes in signalling pathways: insights into insulin actionNat Rev Mol Cell Biol200678596[PubMed][Google Scholar]
107. TantiJFCeppoFJagerJBerthouFImplication of inflammatory signaling pathways in obesity-induced insulin resistanceFront Endocrinol (Lausanne)20123181[PubMed][Google Scholar]
108. TonksNKProtein tyrosine phosphatases: from genes, to function, to diseaseNat Rev Mol Cell Biol20067833846[PubMed][Google Scholar]
109. UchidaTMatozakiTNoguchiTYamaoTHoritaKSuzukiTFujiokaYSakamotoCKasugaMInsulin stimulates the phosphorylation of Tyr538 and the catalytic activity of PTP1C, a protein tyrosine phosphatase with Src homology-2 domainsJ Biol Chem19942691222012228[PubMed][Google Scholar]
110. UekiKKondoTKahnCRSuppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 cause insulin resistance through inhibition of tyrosine phosphorylation of insulin receptor substrate proteins by discrete mechanismsMol Cell Biol20042454345446[PubMed][Google Scholar]
111. UssarSBezyOBluherMKahnCRGlypican-4 enhances insulin signaling via interaction with the insulin receptor and serves as a novel adipokineDiabetes20126122892298[PubMed][Google Scholar]
112. Van HornDJMyersMGJrBackerJMDirect activation of the phosphatidylinositol 3’-kinase by the insulin receptorJ Biol Chem19942692932[PubMed][Google Scholar]
113. WaltermannCKlippEInformation theory based approaches to cellular signalingBiochim Biophys Acta20111810924932[PubMed][Google Scholar]
114. WangJRiedelHInsulin-like growth factor-I receptor and insulin receptor association with a Src homology-2 domain-containing putative adapterJ Biol Chem199827331363139[PubMed][Google Scholar]
115. WangLLRichardSShawASP62 association with RNA is regulated by tyrosine phosphorylationJ Biol Chem199527020102013[PubMed][Google Scholar]
116. WangXChenLMauresTJHerringtonJCarter-SuCSH2-B is a positive regulator of nerve growth factor-mediated activation of the Akt/Forkhead pathway in PC12 cellsJ Biol Chem2004279133141[PubMed][Google Scholar]
117. WangLBalasBChrist-RobertsCYKimRYRamosFJKikaniCKLiCDengCReynaSMusiNPeripheral disruption of the Grb10 gene enhances insulin signaling and sensitivity in vivoMol Cell Biol20072764976505[PubMed][Google Scholar]
118. WatersSBPessinJEInsulin receptor substrate 1 and 2 (IRS1 and IRS2): what a tangled web we weaveTrends Cell Biol1996614[PubMed][Google Scholar]
119. WhiteMFKahnCRThe insulin signaling systemJ Biol Chem199426914[PubMed][Google Scholar]
120. WickMJDongLQHuDLanglaisPLiuFInsulin receptor-mediated p62dok tyrosine phosphorylation at residues 362 and 398 plays distinct roles for binding GTPase-activating protein and Nck and is essential for inhibiting insulin-stimulated activation of Ras and AktJ Biol Chem20012764284342850[PubMed][Google Scholar]
121. WickKRWernerEDLanglaisPRamosFJDongLQShoelsonSELiuFGrb10 inhibits insulin-stimulated insulin receptor substrate (IRS)-phosphatidylinositol 3-kinase/Akt signaling pathway by disrupting the association of IRS-1/IRS-2 with the insulin receptorJ Biol Chem200327884608467[PubMed][Google Scholar]
122. WilliamsJPJoHSacksDBCrimminsDLThomaRSHunnicuttRERaddingWSharmaRKMcDonaldJMTyrosine-phosphorylated calmodulin has reduced biological activityArch Biochem Biophys1994315119126[PubMed][Google Scholar]
123. WongECSacksDBLaurinoJPMcDonaldJMCharacteristics of calmodulin phosphorylation by the insulin receptor kinaseEndocrinology198812318301836[PubMed][Google Scholar]
124. XuHLeeKWGoldfarbMNovel recognition motif on fibroblast growth factor receptor mediates direct association and activation of SNT adapter proteinsJ Biol Chem19982731798717990[PubMed][Google Scholar]
125. YokouchiMSuzukiRMasuharaMKomiyaSInoueAYoshimuraACloning and characterization of APS, an adaptor molecule containing PH and SH2 domains that is tyrosine phosphorylated upon B-cell receptor stimulationOncogene199715715[PubMed][Google Scholar]
126. YuCChenYClineGWZhangDZongHWangYBergeronRKimJKCushmanSWCooneyGJMechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscleJ Biol Chem20022775023050236[PubMed][Google Scholar]
127. ZengLSachdevPYanLChanJLTrenkleTMcClellandMWelshJWangLHVav3 mediates receptor protein tyrosine kinase signaling, regulates GTPase activity, modulates cell morphology, and induces cell transformationMol Cell Biol20002092129224[PubMed][Google Scholar]
128. ZhangWZongCSHermantoULopez-BergamiPRonaiZWangLHRACK1 recruits STAT3 specifically to insulin and insulin-like growth factor 1 receptors for activation, which is important for regulating anchorage-independent growthMol Cell Biol200626413424[PubMed][Google Scholar]