scholarly journals 40 YEARS OF IGF1: IGF1 receptor signaling pathways

2018 ◽  
Vol 61 (1) ◽  
pp. T69-T86 ◽  
Author(s):  
Fumihiko Hakuno ◽  
Shin-Ichiro Takahashi
Keyword(s):  
Signaling Pathways ◽  
Tyrosine Phosphatase ◽  
Sh2 Domain ◽  
Mitogen Activated Protein Kinase ◽  
Regulatory Subunit ◽  
Receptor Signaling ◽  
Α Subunit ◽  
Src Homology ◽  
Igf1 Receptor ◽  
Kinase Pathway

Insulin-like growth factors (IGFs) bind specifically to the IGF1 receptor on the cell surface of targeted tissues. Ligand binding to the α subunit of the receptor leads to a conformational change in the β subunit, resulting in the activation of receptor tyrosine kinase activity. Activated receptor phosphorylates several substrates, including insulin receptor substrates (IRSs) and Src homology collagen (SHC). Phosphotyrosine residues in these substrates are recognized by certain Src homology 2 (SH2) domain-containing signaling molecules. These include, for example, an 85 kDa regulatory subunit (p85) of phosphatidylinositol 3-kinase (PI 3-kinase), growth factor receptor-bound 2 (GRB2) and SH2-containing protein tyrosine phosphatase 2 (SHP2/Syp). These bindings lead to the activation of downstream signaling pathways, PI 3-kinase pathway and Ras-mitogen-activated protein kinase (MAP kinase) pathway. Activation of these signaling pathways is known to be required for the induction of various bioactivities of IGFs, including cell proliferation, cell differentiation and cell survival. In this review, the well-established IGF1 receptor signaling pathways required for the induction of various bioactivities of IGFs are introduced. In addition, we will discuss how IGF signals are modulated by the other extracellular stimuli or by themselves based on our studies.

scholarly journals Gab Docking Proteins in Cardiovascular Disease, Cancer, and Inflammation

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Yoshikazu Nakaoka ◽  
Issei Komuro
Keyword(s):  
Cardiovascular Disease ◽  
Tyrosine Phosphatase ◽  
Sh2 Domain ◽  
Regulatory Subunit ◽  
Special Focus ◽  
Protein Signaling ◽  
Physiological Processes ◽  
Docking Proteins ◽  
Src Homology ◽  
Cancer And Inflammation

The docking proteins of the Grb2-associated binder (Gab) family have emerged as crucial signaling compartments in metazoans. In mammals, the Gab proteins, consisting of Gab1, Gab2, and Gab3, are involved in the amplification and integration of signal transduction evoked by a variety of extracellular stimuli, including growth factors, cytokines, antigens, and other molecules. Gab proteins lack the enzymatic activity themselves; however, when phosphorylated on tyrosine residues, they provide binding sites for multiple Src homology-2 (SH2) domain-containing proteins, such as SH2-containing protein tyrosine phosphatase 2 (SHP2), phosphatidylinositol 3-kinase regulatory subunit p85, phospholipase Cγ, Crk, and GC-GAP. Through these interactions, the Gab proteins transduce signals from activated receptors into pathways with distinct biological functions, thereby contributing to signal diversification. They are known to play crucial roles in numerous physiological processes through their associations with SHP2 and p85. In addition, abnormal Gab protein signaling has been linked to human diseases including cancer, cardiovascular disease, and inflammatory disorders. In this paper, we provide an overview of the structure, effector functions, and regulation of the Gab docking proteins, with a special focus on their associations with cardiovascular disease, cancer, and inflammation.

scholarly journals Targeted Expression of the Class II Phosphoinositide 3-Kinase in Drosophila melanogaster Reveals Lipid Kinase-Dependent Effects on Patterning and Interactions with Receptor Signaling Pathways

2004 ◽  
Vol 24 (2) ◽  
pp. 796-808 ◽  
Author(s):  
Lindsay K. MacDougall ◽  
Mary Elizabeth Gagou ◽  
Sally J. Leevers ◽  
Ernst Hafen ◽  
Michael D. Waterfield
Keyword(s):  
Drosophila Melanogaster ◽  
Signaling Pathways ◽  
Egf Receptor ◽  
Adaptor Protein ◽  
Class Ii ◽  
Notch Receptor ◽  
Mitogen Activated Protein Kinase ◽  
Class I ◽  
Wing Venation ◽  
Receptor Signaling

ABSTRACT Phosphoinositide 3-kinases (PI3Ks) can be divided into three distinct classes (I, II, and III) on the basis of their domain structures and the lipid signals that they generate. Functions have been assigned to the class I and class III enzymes but have not been established for the class II PI3Ks. We have obtained the first evidence for a biological function for a class II PI3K by expressing this enzyme during Drosophila melanogaster development and by using deficiencies that remove the endogenous gene. Wild-type and catalytically inactive PI3K_68D transgenes have opposite effects on the number of sensory bristles and on wing venation phenotypes induced by modified epidermal growth factor (EGF) receptor signaling. These results indicate that the endogenous PI3K_68D may act antagonistically to the EGF receptor-stimulated Ras-mitogen-activated protein kinase pathway and downstream of, or parallel to, the Notch receptor. A class II polyproline motif in PI3K_68D can bind the Drk adaptor protein in vitro, primarily via the N-terminal SH3 domain of Drk. Drk may thus be important for the localization of PI3K_68D, allowing it to modify signaling pathways downstream of cell surface receptors. The phenotypes obtained are markedly distinct from those generated by expression of the Drosophila class I PI3K, which affects growth but not pattern formation.

mSiglec-E, a novel mouse CD33-related siglec (sialic acid-binding immunoglobulin-like lectin) that recruits Src homology 2 (SH2)-domain-containing protein tyrosine phosphatases SHP-1 and SHP-2

2001 ◽  
Vol 353 (3) ◽  
pp. 483-492 ◽  
Author(s):  
Zhenbao YU ◽  
Meryem MAOUI ◽  
Liangtang WU ◽  
Denis BANVILLE ◽  
Shi-Hsiang SHEN
Keyword(s):  
Sialic Acid ◽  
Sequence Similarity ◽  
Tyrosine Phosphatase ◽  
Protein Tyrosine Phosphatases ◽  
Sh2 Domain ◽  
Immunoglobulin Superfamily ◽  
Protein Tyrosine ◽  
Src Homology 2 ◽  
Sialic Acid Binding ◽  
Src Homology

The sialic acid-binding immunoglobulin-like lectins (siglecs) represent a recently defined distinct subset of the immunoglobulin superfamily. By using the Src homology 2 (SH2)-domain-containing protein tyrosine phosphatase SHP-1 as bait in a yeast two-hybrid screen, we have identified a new member of the mouse siglec family, mSiglec-E. The mSiglec-E cDNA encodes a protein of 467 amino acids that contains three extracellular immunoglobulin-like domains, a transmembrane region and a cytoplasmic tail bearing two immunoreceptor tyrosine-based inhibitory motifs (ITIMs). mSiglec-E is highly expressed in mouse spleen, a tissue rich in leucocytes. The ITIMs of mSiglec-E can recruit SHP-1 and SHP-2, two inhibitory regulators of immunoreceptor signal transduction. This suggests that the function of mSiglec-E is probably an involvement in haematopoietic cells and the immune system as an inhibitory receptor. When expressed in COS-7 cells, mSiglec-E was able to mediate sialic acid-dependent binding to human red blood cells, suggesting that mSiglec-E may function through cell–cell interactions. In comparison with the known members of the siglec family, mSiglec-E exhibits a high degree of sequence similarity to both human siglec-7 and siglec-9. The gene encoding mSiglec-E is localized in the same chromosome as that encoding mouse CD33. Phylogenetic analysis reveals that neither mouse mSiglec-E nor CD33 shows a clear relationship with any human siglecs so far identified.

scholarly journals Lnk inhibits erythropoiesis and Epo-dependent JAK2 activation and downstream signaling pathways

Blood ◽  
2005 ◽  
Vol 105 (12) ◽  
pp. 4604-4612 ◽  
Author(s):  
Wei Tong ◽  
Jing Zhang ◽  
Harvey F. Lodish
Keyword(s):  
Signaling Pathways ◽  
Fetal Liver ◽  
Adaptor Protein ◽  
Sh2 Domain ◽  
Janus Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Ph Domain ◽  
Erythroid Progenitors ◽  
Inhibitory Function ◽  
C Terminus

Abstract Erythropoietin (Epo), along with its receptor EpoR, is the principal regulator of red cell development. Upon Epo addition, the EpoR signaling through the Janus kinase 2 (JAK2) activates multiple pathways including Stat5, phosphoinositide-3 kinase (PI-3K)/Akt, and p42/44 mitogen-activated protein kinase (MAPK). The adaptor protein Lnk is implicated in cytokine receptor signaling. Here, we showed that Lnk-deficient mice have elevated numbers of erythroid progenitors, and that splenic erythroid colony-forming unit (CFU-e) progenitors are hypersensitive to Epo. Lnk-/- mice also exhibit superior recovery after erythropoietic stress. In addition, Lnk deficiency resulted in enhanced Epo-induced signaling pathways in splenic erythroid progenitors. Conversely, Lnk overexpression inhibits Epo-induced cell growth in 32D/EpoR cells. In primary culture of fetal liver cells, Lnk overexpression inhibits Epo-dependent erythroblast differentiation and induces apoptosis. Lnk blocks 3 major signaling pathways, Stat5, Akt, and MAPK, induced by Epo in primary erythroblasts. In addition, the Lnk Src homology 2 (SH2) domain is essential for its inhibitory function, whereas the conserved tyrosine near the C-terminus and the pleckstrin homology (PH) domain of Lnk are not critical. Furthermore, wild-type Lnk, but not the Lnk SH2 mutant, becomes tyrosine-phosphorylated following Epo administration and inhibits EpoR phosphorylation and JAK2 activation. Hence, Lnk, through its SH2 domain, negatively modulates EpoR signaling by attenuating JAK2 activation, and regulates Epo-mediated erythropoiesis. (Blood. 2005; 105:4604-4612)

scholarly journals Differential inhibition of signaling pathways by dominant-negative SH2/SH3 adapter proteins.

1995 ◽  
Vol 15 (12) ◽  
pp. 6829-6837 ◽  
Author(s):  
M Tanaka ◽  
R Gupta ◽  
B J Mayer
Keyword(s):  
Protein Kinase ◽  
Signaling Pathways ◽  
Tyrosine Kinases ◽  
Egf Receptor ◽  
Sh3 Domain ◽  
Sh2 Domain ◽  
Dominant Negative ◽  
Mitogen Activated Protein Kinase ◽  
Erk Activation ◽  
Mitogen Activated Protein

SH2/SH3 adapters are thought to function in signal transduction pathways by coupling inputs from tyrosine kinases to downstream effectors such as Ras. Members of the mitogen-activated protein kinase family are known to be activated by a variety of mitogenic stimuli, including tyrosine kinases such as Abl and the epidermal growth factor (EGF) receptor. We have used activation of the mitogen-activated protein kinase Erk-1 as a model system with which to examine whether various dominant-negative SH2/SH3 adapters (Grb2, Crk, and Nck) could block signaling pathways leading to Erk activation. Activation of Erk-1 by oncogenic Abl was effectively inhibited by Grb2 with mutations in either its SH2 or SH3 domain or by Crk-1 with an SH3 domain mutation. The Crk-1 SH2 mutant was less effective, while Nck SH2 and SH3 mutants had little or no effect on Erk activation. These results suggest that both Crk and Grb2 may contribute to the activation of Erk by oncogenic Abl, whereas Nck is unlikely to participate in this pathway. Next we examined whether combinations of these dominant-negative adapters could inhibit Erk activation more effectively than each mutant alone. When combinations of Crk-1 and Grb2 mutants were analyzed, the combination of the Crk-1 SH3 mutant plus the Grb2 SH3 mutant gave a striking synergistic effect. This finding suggests that in Abl-transformed cells, more than one class of tyrosine-phosphorylated sites (those that bind the Grb2 SH2 domain and those that bind the Crk SH2 domain) can lead to Ras activation. In contrast to results with Abl, Erk activation by EGF was strongly inhibited only by Grb2 mutants; Crk and Nck mutants had little or no effect. This finding suggests that Grb2 is the only adapter involved in the activation of Erk by EGF. Dominant-negative adaptors provide a novel means to identify binding interactions important in vivo for signaling in response to a variety of stimuli.

scholarly journals Recruitment of the Tyrosine Phosphatase Src Homology 2 Domain Tyrosine Phosphatase-2 to the p85 Subunit of Phosphatidylinositol-3 (PI-3) Kinase Is Required for Insulin-Like Growth Factor-I-Dependent PI-3 Kinase Activation in Smooth Muscle Cells

Endocrinology ◽  
2006 ◽  
Vol 147 (3) ◽  
pp. 1458-1465 ◽  
Author(s):  
Mijin Kwon ◽  
Yan Ling ◽  
Laura A. Maile ◽  
Jane Badley-Clark ◽  
David R. Clemmons
Keyword(s):  
Smooth Muscle ◽  
Cell Migration ◽  
Tyrosine Phosphatase ◽  
Insulin Receptor Substrate ◽  
Kinase Activation ◽  
Src Homology 2 ◽  
Igf I ◽  
Src Homology ◽  
Src Homology 2 Domain ◽  
Kinase Pathway

IGF-I stimulates smooth muscle cell (SMC) migration and the phosphatidylinositol-3 (PI-3) kinase pathway plays an important role in mediating the IGF-I-induced migratory response. Prior studies have shown that the tyrosine phosphatase Src homology 2 domain tyrosine phosphatase (SHP)-2 is necessary to activate PI-3 kinase in response to growth factors and expression of a phosphatase inactive form of SHP-2 (SHP-2/C459S) impairs IGF-I-stimulated cell migration. However, the mechanism by which SHP-2 phosphatase activity or the recruitment of SHP-2 to other signaling molecules contributes to IGF-I stimulated PI-3 kinase activation has not been determined. SMCs that had stable expression of SHP-2/C459S had reduced cell migration and Akt activation in response to IGF-I, compared with SMC-expressing native SHP-2. Similarly in cells expressing native SHP-2, IGF-I induced SHP-2 binding to p85, whereas in cells expressing SHP-2/C459S, there was no increase. Because the C459S substitution results in loss of the ability of SHP-2 to disassociate from its substrates, making it inaccessible not only to p85 but also the other proteins, a p85 mutant in which tyrosines 528 and 556 were changed to phenylalanines was prepared to determine whether this would disrupt the p85/SHP-2 interaction and whether the loss of this specific interaction would alter IGF-I stimulated the cell migration. Substitution for these tyrosines in p85 resulted in loss of SHP-2 recruitment and was associated with a reduction in association of the p85/p110 complex with insulin receptor substrate-1. Cells stably expressing this p85 mutant also showed a decrease in IGF-I-stimulated PI-3 kinase activity and cell migration. Preincubation of cells with a cell-permeable peptide that contains the tyrosine556 motif of p85 also disrupted SHP-2 binding to p85 and inhibited the IGF-I-induced increase in cell migration. The findings indicate that tyrosines 528 and 556 in p85 are required for SHP-2 association. SHP-2 recruitment to p85 is required for IGF-I-stimulated association of the p85/p110 complex with insulin receptor substrate-1 and for the subsequent activation of the PI-3 kinase pathway leading to increased cell migration.

scholarly journals Src Homology 2 Domain-Containing Protein Tyrosine Phosphatase Promotes Inflammation and Accelerates Osteoarthritis by Activating β-Catenin

2021 ◽  
Vol 9 ◽  
Author(s):  
Tenghui Tao ◽  
Danni Luo ◽  
Chenghao Gao ◽  
Hui Liu ◽  
Zehua Lei ◽  
...  
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Cartilage Degradation ◽  
Mitogen Activated Protein Kinase ◽  
Osteophyte Formation ◽  
Protein Tyrosine ◽  
Src Homology 2 ◽  
Primary Mouse ◽  
Src Homology ◽  
Src Homology 2 Domain

Osteoarthritis (OA) is a chronic articular disease characterized by cartilage degradation, subchondral bone remodeling and osteophyte formation. Src homology 2 domain-containing protein tyrosine phosphatase (SHP2) has not been fully investigated in the pathogenesis of OA. In this study, we found that SHP2 expression was significantly increased after interleukin-1β (IL-1β) treatment in primary mouse chondrocytes. Inhibition of SHP2 using siRNA reduced MMP3, MMP13 levels, but increased AGGRECAN, COL2A1, SOX9 expression in vitro. On the contrary, overexpression of SHP2 exerted the opposite results and promoted cartilage degradation. Mechanistically, SHP2 activated Wnt/β-catenin signaling possibly through directly binding to β-catenin. SHP2 also induced inflammation through activating Mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) pathways. Our in vivo studies showed that SHP2 knockdown effectively delayed cartilage destruction and reduced osteophyte formation in the mouse model of OA induced by destabilization of the medial meniscus (DMM). Altogether, our study identifies that SHP2 is a novel and potential therapeutic target of OA.

Identification and characterization of a high-affinity interaction between v-Crk and tyrosine-phosphorylated paxillin in CT10-transformed fibroblasts

1993 ◽  
Vol 13 (8) ◽  
pp. 4648-4656
Author(s):  
R B Birge ◽  
J E Fajardo ◽  
C Reichman ◽  
S E Shoelson ◽  
Z Songyang ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Tyrosine Phosphorylation ◽  
Cell Transformation ◽  
Tyrosine Phosphatase ◽  
State Level ◽  
Sh2 Domain ◽  
Sequence Specificity ◽  
Src Homology

The genome of avian sarcoma virus CT10 encodes a fusion protein in which viral Gag sequences are fused to cellular Crk sequences containing primarily Src homology 2 (SH2) and Src homology 3 (SH3) domains. Transformation of chicken embryo fibroblasts (CEF) with the Gag-Crk fusion protein results in the elevation of tyrosine phosphorylation on specific cellular proteins with molecular weights of 130,000, 110,000, and 70,000 (p130, p110, and p70, respectively), an event which has been correlated with cell transformation. In this study, we have identified the 70-kDa tyrosine-phosphorylated protein in CT10-transformed CEF (CT10-CEF) as paxillin, a cytoskeletal protein suggested to be important for organizing the focal adhesion. Tyrosine-phosphorylated paxillin was found to be complexed with v-Crk in vivo as evident from coimmunoprecipitation studies. Moreover, a bacterially expressed recombinant glutathione S-transferase (GST)-CrkSH2 fragment bound paxillin in vitro with a subnanomolar affinity, suggesting that the SH2 domain of v-Crk is sufficient for binding. Mapping of the sequence specificity of a GST-CrkSH2 fusion protein with a partially degenerate phosphopeptide library determined a motif consisting of pYDXP, and in competitive coprecipitation studies, an acetylated A(p)YDAPA hexapeptide was able to quantitatively inhibit the binding of GST-CrkSH2 to paxillin and p130, suggesting that it meets the minimal structural requirements necessary for the interaction of CrkSH2 with physiological targets. To investigate the mechanism by which v-Crk elevates the tyrosine phosphorylation of paxillin in vivo, we have treated normal CEF and CT10-CEF with sodium vanadate to inhibit protein tyrosine phosphatase activity. These data suggest that paxillin is involved in a highly dynamic kinase-phosphatase interplay in normal CEF and that v-Crk binding may interrupt this balance to increase the steady-state level of tyrosine phosphorylation. By contrast, the 130-kDa protein was not tyrosine phosphorylated upon vanadate treatment of normal CEF and only weakly affected in the CT10-CEF, suggesting that a different mechanism may be involved in its phosphorylation.

The SH2 domain is required for stable phosphorylation of p56lck at tyrosine 505, the negative regulatory site

1993 ◽  
Vol 13 (11) ◽  
pp. 7112-7121
Author(s):  
F G Gervais ◽  
L M Chow ◽  
J M Lee ◽  
P E Branton ◽  
A Veillette
Keyword(s):  
Tyrosine Phosphatase ◽  
Sh2 Domain ◽  
Tyrosine Residue ◽  
Catalytic Function ◽  
Inhibitory Site ◽  
Tyrosine Protein Kinase ◽  
Src Homology ◽  
Carboxy Terminal ◽  
Nih 3T3

The catalytic function of Src-related tyrosine protein kinases is repressed by phosphorylation of a conserved carboxy-terminal tyrosine residue. Recent studies suggest that this inhibitory event is not the result of autophosphorylation but that it is mediated by another cytoplasmic tyrosine protein kinase, termed p50csk. In this report, we have evaluated the processes regulating the extent of phosphorylation of the inhibitory carboxy-terminal tyrosine residue of p56lck, a lymphocyte-specific member of the Src family. By analyzing kinase-defective variants of p56lck expressed in mouse NIH 3T3 cells, we have found that the noncatalytic Src homology 2 (SH2) domain, but not the SH3 sequence or the sites of Lck myristylation and autophosphorylation, is necessary for stable phosphorylation at the carboxy-terminal tyrosine 505. Further studies in which Lck and Csk were coexpressed in S. cerevisiae indicated that the absence of the SH2 domain did not affect the ability of Csk to phosphorylate p56lck at tyrosine 505. However, we observed that incubation of cells with the tyrosine phosphatase inhibitor pervanadate restored the tyrosine 505 phosphorylation of Lck polypeptides devoid of the SH2 motif. Additionally, the presence of the SH2 sequence protected tyrosine 505 from in vitro dephosphorylation by the hemopoietic tyrosine protein phosphatase CD45. Taken together, these findings raised the possibility that the SH2 motif contributes to the physiological suppression of the catalytic function of p56lck at least in part through its ability to stabilize phosphorylation at the inhibitory site.

Phosphatase inhibition promotes antiapoptotic but not proliferative signaling pathways in erythropoietin-dependent HCD57 cells

Blood ◽  
2000 ◽  
Vol 96 (6) ◽  
pp. 2084-2092
Author(s):  
Amy E. Lawson ◽  
Haifeng Bao ◽  
Amittha Wickrema ◽  
Sarah M. Jacobs-Helber ◽  
Stephen T. Sawyer
Keyword(s):  
Tyrosine Phosphatase ◽  
Critical Role ◽  
Mitogen Activated Protein Kinase ◽  
Phosphatidylinositol 3 Kinase ◽  
Erythroid Progenitors ◽  
Murine Cell Line ◽  
Mitogen Activated Protein ◽  
Erk Activity ◽  
Kinase Pathway

Erythropoietin (EPO) allows erythroid precursors to proliferate while protecting them from apoptosis. Treatment of the EPO-dependent HCD57 murine cell line with 70 μmol/L orthovanadate, a tyrosine phosphatase inhibitor, resulted in both increased tyrosine protein phosphorylation and prevention of apoptosis in the absence of EPO without promoting proliferation. Orthovanadate also delayed apoptosis in primary human erythroid progenitors. Thus, we investigated what survival signals were activated by orthovanadate treatment. Expression of Bcl-XL and BAD phosphorylation are critical for the survival of erythroid cells, and orthovanadate in the absence of EPO both maintained expression levels of antiapoptotic Bcl-XLand induced BAD phosphorylation at serine 112. Orthovanadate activated JAK2, STAT1, STAT5, the phosphatidylinositol-3 kinase (PI-3 kinase) pathway, and other signals such as JNK and p38 without activating the EPO receptor, JAK1, Tyk2, Vav, STAT3, and SHC. Neither JNK nor p38 appeared to have a central role in either apoptosis or survival induced by orthovanadate. Treatment with cells with LY294002, an inhibitor of PI-3 kinase activity, triggered apoptosis in orthovanadate-treated cells, suggesting a critical role of PI-3 kinase in orthovanadate-stimulated survival. Mitogen-activated protein kinase (MAPK) was poorly activated by orthovanadate, and inhibition of MAPK with PD98059 blocked proliferation without inducing apoptosis. Thus, orthovanadate likely acts to greatly increase JAK/STAT and PI-3 kinase basal activity in untreated cells by blocking tyrosine protein phosphatase activity. Activated JAK2/STAT5 then likely acts upstream of Bcl-XL expression and PI-3 kinase likely promotes BAD phosphorylation to protect from apoptosis. In contrast, MAPK/ERK activity correlates with only EPO-dependent proliferation but is not required for survival of HCD57 cells.

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