Search results for IRS1
Showing 30 results out of 34
Reaction (30 results from a total of 34)
Identifier: R-HSA-9842666
Species:
Homo sapiens
Compartment:
plasma membrane,
cytosol
In the context of a chimeric EGFR-LTK receptor, IRS1 is phosphorylated after stimulation with EGF (Ueno et al, 1995; Ueno et al, 1996). Phosphorylated IRS1 appears to contribute to MAPK signaling by the chimeric receptor by recruiting GRB2; abrogation of the IRS1 tyrosine binding site on the LTK receptor decreases phosphorylation of MAPK1 and MAPK3 and mitogenic activity in BaF3 cells (Ueno et al, 1995; Ueno et al, 1996).
Identifier: R-HSA-9700168
Species:
Homo sapiens
Compartment:
plasma membrane,
cytosol
IRS1 is phosphorylated downstream of active ALK in a manner that is dependent on ALK kinase activity. Based on studies in NPM-ALK fusions, ALK likely phosphorylates IRS1 on one or more tyrosine residues, but the target amino acid(s) have not been identified directly in the context of the full-length ALK receptor (Fujimoto et al 1996; Stoica et al, 2001; Motegi et al, 2004; reviewed in Roskoski, 2013; Delle Corte et al, 2018). ALK-dependent IRS1 phosphorylation activates the MAP kinase signaling pathway and promotes cellular proliferation, but direct binding of a RAS GEF such as GRB2:SOS1 has not been shown (reviewed in Turner and Alexander, 2006; Chiarle et al, 2008; Roskoski, 2013).
Identifier: R-HSA-9603437
Species:
Homo sapiens
Compartment:
plasma membrane,
cytosol
Activated wild-type NTRK3 (TRKC), as well as constitutively active ETV6-NTRK3 oncogene, a product of translocation between ETV6 and NTRK3 gene loci in congenital fibrosarcoma and cellular mesoblastic nephroma, are able to bind to adaptor protein IRS1 (Morrison et al. 2002, Lannon et al. 2004, Jin et al. 2008). Binding of IRS1 to NTRK3 is enhanced in the presence of SRC (Jin et al. 2008).
Identifier: R-HSA-9712082
Species:
Homo sapiens
Compartment:
plasma membrane,
cytosol
IRS1 is phosphorylated downstream of NPM-ALK fusions (Fujimoto et al, 1996). ALK-dependent IRS phosphorylation activates the MAP kinase signaling pathway and promotes cellular proliferation, but direct binding of a RAS GEF such as GRB2:SOS1 has not been shown (reviewed in Chiarle et al, 2008; Roskoski, 2013).
Identifier: R-HSA-9842671
Species:
Homo sapiens
Compartment:
plasma membrane,
cytosol
MAPK phosphorylation is observed downstream of both activated full length LTK and activated chimeric receptors of LTK (Ueno et al, 1995; Ueno et al, 1996; Honda et al, 1999; Yamada et al, 2008; Farhan et al, 2010; Roll and Reuther, 2012).
Binding site studies with chimeric proteins identified two NPXY sites in LTK that appear to contribute to MAPK signaling, one at the C-terminus including the SHC-binding Y862 and one closer to the juxtamembrane region including Y485, that appears to recruit IRS1 (Ueno et al, 1995; Ueno et al, 1996). IRS1 is pulled down with stimulated chimeric LTK receptors and undergoes phosphorylation; these interactions are not observed with a Y485F chimeric receptor. IRS appears to contribute to the recruitment of GRB2 and SYP, and mutation of Y485 either singly or in combination with Y862 decreases the mitogenic activity, RAS signaling and phosphorylation of MAPK1 and MAPK3 (Ueno et al, 1995; Ueno et al, 1996). These protein interactions remain to be confirmed in the context of the full length LTK receptor.
Co-immunoprecipitation studies show that GRB2 and SOS1 are pulled down with SHC1 and the activated EGFR:LTK and CSF1R receptor chimeras (Ueno et al, 1995; Ueno et al, 1996). Mutation of the SHC binding site Y862 decreases signaling through the MAPK pathway, suggesting that the complex assembled by this site contributes to the phosphorylation of MAPK proteins and mitogenic signaling (Ueno et al, 1996).
Binding site studies with chimeric proteins identified two NPXY sites in LTK that appear to contribute to MAPK signaling, one at the C-terminus including the SHC-binding Y862 and one closer to the juxtamembrane region including Y485, that appears to recruit IRS1 (Ueno et al, 1995; Ueno et al, 1996). IRS1 is pulled down with stimulated chimeric LTK receptors and undergoes phosphorylation; these interactions are not observed with a Y485F chimeric receptor. IRS appears to contribute to the recruitment of GRB2 and SYP, and mutation of Y485 either singly or in combination with Y862 decreases the mitogenic activity, RAS signaling and phosphorylation of MAPK1 and MAPK3 (Ueno et al, 1995; Ueno et al, 1996). These protein interactions remain to be confirmed in the context of the full length LTK receptor.
Co-immunoprecipitation studies show that GRB2 and SOS1 are pulled down with SHC1 and the activated EGFR:LTK and CSF1R receptor chimeras (Ueno et al, 1995; Ueno et al, 1996). Mutation of the SHC binding site Y862 decreases signaling through the MAPK pathway, suggesting that the complex assembled by this site contributes to the phosphorylation of MAPK proteins and mitogenic signaling (Ueno et al, 1996).
Identifier: R-HSA-9842655
Species:
Homo sapiens
Compartment:
plasma membrane,
cytosol
In the context of a chimeric EGFR:LTK receptor, ligand-dependent autophosphorylation of Y485 appears to support the formation of an IRS1:GRB2 complex that promotes RAS signaling through the activated receptor. These results remain to be validated in the context of a full length LTK receptor with physiological ligand however (Ueno et al, 1995; Ueno et al, 1996).
Identifier: R-HSA-9700156
Species:
Homo sapiens
Compartment:
plasma membrane,
cytosol
Phosphorylated tyrosine 1096 is the docking site for IRS1 on the active full length- ALK receptor. IRS-mediated signaling simulates the MAP kinase and PI3K pathways and contributes to cellular proliferation in a manner that depends on ALK kinase activity (Motegi et al, 2004; Kuo et al, 2007; reviewed in Turner and Alexander, 2006; Roskoski, 2013; Della Corte et al, 2018).
Identifier: R-HSA-74747
Species:
Homo sapiens
Compartment:
cytosol
At the beginning of this reaction, 1 molecule of 'phospho-IRS' is present. At the end of this reaction, 1 molecule of 'Orthophosphate', and 1 molecule of 'IRS' are present.
This reaction takes place in the 'cytosol' and is mediated by the 'protein tyrosine phosphatase activity' of 'protein tyrosine phosphatase' (Pederson et al.2001).
This reaction takes place in the 'cytosol' and is mediated by the 'protein tyrosine phosphatase activity' of 'protein tyrosine phosphatase' (Pederson et al.2001).
Identifier: R-HSA-74737
Species:
Homo sapiens
Compartment:
cytosol
IRS1, IRS2 and IRS3 are all known to bind the regulatory subunit of PI3K via its SH2 domain, an interaction that itself activates the kinase activity of the PI3K catalytic subunit (Rivachandran et al. 2001).
Identifier: R-HSA-198211
Species:
Homo sapiens
Compartment:
cytoplasmic side of plasma membrane
IRS1 and IRS2 bind directly to TRK receptors phosphorylated at Y490, through their phosphotyrosine- binding (PTB) domains.
Identifier: R-HSA-2671873
Species:
Homo sapiens
Compartment:
plasma membrane,
cytosol
SH2B1 in the LEP:LEPR:JAK2:SH2B1 complex can bind either IRS1 or IRS2 (Duan et al. 2004, Li et al. 2007). The binding brings IRS1/2 into proximity with JAK2 for phosphorylation.
Identifier: R-HSA-74736
Species:
Homo sapiens
Compartment:
cytosol
Inactive p21ras:GDP is anchored to the plasma membrane by a farnesyl residue. Insulin stimulation results in phosphorylation of IRS1/2 on tyrosine residues. GRB2 binds the phosphotyrosines via its SH2 domain. As IRS is phosphorylated by the insulin receptor near to the plasma membrane, the GRB2:SOS1:IRS interaction brings SOS1 and p21 Ras into close proximity.
Identifier: R-HSA-5686315
Species:
Homo sapiens
Compartment:
cytosol
p-Y-IRS1,p-Y-IRS2 dissociates from GRB2-1:p-4S-SOS1
Identifier: R-HSA-109823
Species:
Homo sapiens
Compartment:
cytosol
At the beginning of this reaction, 4 molecules of 'ATP', and 1 molecule of 'GRB2:SOS:IRS-P' are present. At the end of this reaction, 1 molecule of 'GRB2:IRS-P', 1 molecule of 'phospho-SOS', and 4 molecules of 'ADP' are present.
This reaction takes place on the 'internal side of plasma membrane' and is mediated by the 'kinase activity' of 'ERK1'.
This reaction takes place on the 'internal side of plasma membrane' and is mediated by the 'kinase activity' of 'ERK1'.
Identifier: R-HSA-109817
Species:
Homo sapiens
Compartment:
plasma membrane,
cytosol
SOS promotes the formation of GTP-bound RAS, thus activating this protein. RAS activation results in activation of the protein kinases RAF1, B-Raf, and MAP-ERK kinase kinase (MEKK), and the catalytic subunit of PI3K, as well as of a series of RALGEFs. The activation cycle of RAS GTPases is regulated by their interaction with specific guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). GEFs promote activation by inducing the release of GDP, whereas GAPs inactivate RAS-like proteins by stimulating their intrinsic GTPase activity. NGF-induced RAS activation via SHC-GRB2-SOS is maximal at 2 min but it is no longer detected after 5 min. Therefore, the transient activation of RAS obtained through SHC-GRB2-SOS is insufficient for the prolonged activation of ERKs found in NGF-treated cells.
Identifier: R-HSA-8983003
Species:
Homo sapiens
Compartment:
cytosol,
extracellular region,
plasma membrane
Insulin receptor substrate 1 and 2 (IRS1, IRS2) bind to activated Interleukin-7 receptor complex . Interleukin-7 (IL7) stimulation of human thymocytes results in the rapid tyrosine phosphorylation of IRS1 and IRS2.
This is a black box event because the kinase responsible for IRS phosphorylation is unclear.
Identifier: R-HSA-2428930
Species:
Homo sapiens
Compartment:
plasma membrane
IRS1 binds the NPEY-juxtamembrane motif of phosphorylated IGF1R (Craparo et al. 1995, He et al. 1995, Huang et al. 2001). IRS4 is also involved in signaling by IGF1R and is presumed to bind phosphorylated IGF1R in the same way as IRS1 (Qu et al. 1999, Cuevas et al. 2007). IRS1 and IRS4 are located at the plasma membrane (Karlsson et al. 2004, Fantin et al. 1998).
Identifier: R-HSA-2428926
Species:
Homo sapiens
Compartment:
plasma membrane,
cytosol
Phosphorylated IGF1R phosphorylates IRS1 (Siemeister et al. 1995, Xu et al. 1995, Takahashi et al. 1997, Rakatzi et al. 2006), IRS2 (Kim et al. 1998, Kim et al. 2004), and IRS4 (Fantin et al.1998, Karas et al. 2001, Cuevas et al. 2007) on numerous tyrosine residues. IRS4 is phosphorylated by IGF1R in HEK cells but not in primary muscle cells (Fantin et al. 1998, Schreyer et al. 2003). The phosphotyrosine resideus create binding sites for downstream effectors such as GRB2:SOS and PI3K.
Identifier: R-HSA-74707
Species:
Homo sapiens
Compartment:
plasma membrane,
cytosol
Using receptor mutagenesis studies it is known that IRS1 via its PTB domain binds to the insulin receptor at the juxtamembrane region at tyrosine 972. The interaction is further stabilized by the PH domain of IRS1 which interacts with the phospholipids of the plasma membrane. This allows the receptor to phosphorylate IRS1 on up to 13 of its tyrosine residues (Tavare and Denton 1998, Duan et al.2004).
Identifier: R-HSA-2671862
Species:
Homo sapiens
Compartment:
plasma membrane,
cytosol
JAK2 phosphorylates IRS1/2 after IRS1/2 binds SH2B1 in the LEP:LEPR:JAK2:SH2B1 complex (Martin-Romero and Sanchez-Margalet 2001, Li et al. 2007). However, in some cells leptin may only affect phosphorylation of IRS1/2 when insulin signaling subsequently occurs (Szanto and Kahn 2000). As inferred from mouse and rat (Buettner et al. 2008, Hill et al. 2008) phosphorylated IRS1/2 then activates PI3K independently of STAT3 signaling.
Identifier: R-HSA-9712088
Species:
Homo sapiens
Compartment:
cytosol
IRS1 binds the NPM-ALK fusion protein through tyrosine residue 167. Mutation of this residue abrogates IRS1 binding, but the NPM-ALK Y167 mutant is still able to support the transforming activity of the fusion protein (Fujimoto et al, 1996).
Identifier: R-HSA-198295
Species:
Homo sapiens
Compartment:
cytoplasmic side of plasma membrane
IRS1 and IRS2 are tyrosine phosphorylated at multiple YXXM motifs by the active TRKA kinase (Miranda et al.2001).
Identifier: R-HSA-2428922
Species:
Homo sapiens
Compartment:
cytosol,
plasma membrane
IRS2 binds the NPEY-juxtamembrane motif of phosphorylated IGF1R (He et al. 1996, Kim et al. 1998). IRS2 is cytosolic while IRS1 and IRS4 are located in the plasma membrane.
Identifier: R-HSA-2671872
Species:
Homo sapiens
Compartment:
plasma membrane,
cytosol
The SH2 domain of SH2B1 binds phosphotyrosine-813 of JAK2 (Nishi et al. 2005, Li et al. 2007). Binding of SH2B1 to JAK2 enhances leptin-induced JAK2 activity. SH2B1 also recruits IRS1 for phosphorylation by JAK2 (Li et al. 2007).
Identifier: R-HSA-9603445
Species:
Homo sapiens
Compartment:
plasma membrane,
cytosol
Activation of PI3K signaling downstream of NTRK3 (TRKC) is evident from PI3K-dependent activating phosphorylation of AKT in response to NTRK3 activity. SRC and IRS1 contribute to NTRK3-mediated induction of PI3K activity, but the exact mechanism is not known (Tognon et al. 2001, Jin et al. 2008).
Identifier: R-HSA-9667914
Species:
Homo sapiens
Compartment:
extracellular region,
plasma membrane
ALK receptor tyrosine kinase binds to secreted growth factor midkine (MDK), homologous to pleiotrophin (PTN) (Stoica et al, 2002). MDK activates PI3K signaling (Stoica et al. 2002) and IRS1/NFKB signaling (Kuo et al, 2007) downstream of ALK.
Identifier: R-HSA-201486
Species:
Homo sapiens
Compartment:
extracellular region,
plasma membrane
Pleiotrophin (PTN) is a secreted growth factor that induces neurite outgrowth. The receptor tyrosine kinase anaplastic lymphoma kinase (ALK) binds PTN and transduces PTN-mediated signals through RAS, PI3K, PLCG1 and IRS1 (Stoica et al. 2001, Bowden et al. 2002), as well as through GSK3B/CTTNB1 (Yanagisawa et al. 2010).
Identifier: R-HSA-198315
Species:
Homo sapiens
Compartment:
cytoplasmic side of plasma membrane
The PI3K regulatory subunit p85 binds to IRS1 or IRS2, tyrosine-phosphorylated at YXXM motifs, through its SH2 domain.
As the p85 subunt is constitutively associated with the p110 catalytic subunit, the outcome is that the whole PI3K complex is recruited to the membrane. The interaction at the plasma membrane of the p85 regulatory subunit with the p110 catalytic subunit of PI3K (phosphatidylinositol-4,5-bisphosphate 3-kinase) causes a conformational change, resulting in activation of the catalytic subunit (Miranda et al. 2001).
As the p85 subunt is constitutively associated with the p110 catalytic subunit, the outcome is that the whole PI3K complex is recruited to the membrane. The interaction at the plasma membrane of the p85 regulatory subunit with the p110 catalytic subunit of PI3K (phosphatidylinositol-4,5-bisphosphate 3-kinase) causes a conformational change, resulting in activation of the catalytic subunit (Miranda et al. 2001).
Identifier: R-HSA-74712
Species:
Homo sapiens
Compartment:
plasma membrane,
cytosol
At the beginning of this reaction, 1 molecule of 'phospho-IRS:activated insulin receptor' is present. At the end of this reaction, 1 molecule of 'activated insulin receptor', and 1 molecule of 'phospho-IRS' are present.
This reaction takes place on the 'internal side of plasma membrane'. In Fao or NIH3T3 cells stably expressing IR, overexpression of PKCζ enhances the dissociation from IR and decrease in IRS1 tyrosine phosphorylation caused by prolonged insulin stimulation (Riu et al. 2001, Ravichandran et al. 2001).
This reaction takes place on the 'internal side of plasma membrane'. In Fao or NIH3T3 cells stably expressing IR, overexpression of PKCζ enhances the dissociation from IR and decrease in IRS1 tyrosine phosphorylation caused by prolonged insulin stimulation (Riu et al. 2001, Ravichandran et al. 2001).
Identifier: R-HSA-9842665
Species:
Homo sapiens
Compartment:
cytosol,
plasma membrane
Full-length LTK binds to the cytoplasmic tyrosine kinase TNK2 (also known as ACK) indirectly through GRB2 (Pao-Chun et al, 2009). It is possible that this interaction is promoted by one or both of the two NPXY sites in LTK that are believed to recruit GRB2 (Y485, through IRS1 or Y862 through SHC1), but this has not been tested (Ueno et al, 1995; Ueno et al, 1996). In other contexts, TNK2 contributes to cell spreading, metastasis and migration, but its possible role in LTK signaling remains to be clarified (Lougheed et al, 2004; Eisenmann et al, 1999; Modzelewska et al, 2006).
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