IRS-1 acts as an endocytic regulator of IGF-I receptor to facilitate sustained IGF signaling

Yoneyama, Yoshimasa; Lanzerstorfer, Peter; Niwa, Hideaki; Umehara, Takashi; Shibano, Takashi; Yokoyama, Shigeyuki; Chida, Kazuhiro; Weghuber, Julian; Hakuno, Fumihiko; Takahashi, Shinichiro

doi:10.7554/elife.32893

Cited by 45 publications

(37 citation statements)

References 80 publications

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“…The molecular basis for the close interactions between IGF-IR endocytosis and its signaling components is still poorly understood. Recently, it has been suggested that the ability of insulin receptor substrate-1 (IRS-1) to interact with the clathrin adapter protein AP2, which is essential for endocytosis, plays an important role in IGF-IR internalization [28]. Overexpression of IRS-I resulted in the accumulation of activated IGF-IR at the cellular membrane [28].…”

Section: The Igf-ir and Endocytosismentioning

confidence: 99%

“…Recently, it has been suggested that the ability of insulin receptor substrate-1 (IRS-1) to interact with the clathrin adapter protein AP2, which is essential for endocytosis, plays an important role in IGF-IR internalization [28]. Overexpression of IRS-I resulted in the accumulation of activated IGF-IR at the cellular membrane [28]. Conversely, knockdown of IRS-I induced faster internalization of IGF-IRs [28].…”

Section: The Igf-ir and Endocytosismentioning

confidence: 99%

“…Overexpression of IRS-I resulted in the accumulation of activated IGF-IR at the cellular membrane [28]. Conversely, knockdown of IRS-I induced faster internalization of IGF-IRs [28]. These data suggest that IRS-1 inhibits the recruitment of IGF-IR into clathrin-coated structures; the ability of IRS-I to bind to AP-2 avoids rapid endocytosis of the IGF-IR and prolongs its activity at the cell surface in HEK293T cells [28] ( Figure 2A).…”

Section: The Igf-ir and Endocytosismentioning

confidence: 99%

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New Insights from IGF-IR Stimulating Activity Analyses: Pathological Considerations

Janssen

2020

Cells

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Insulin-like growth factor-I (IGF-I) and insulin-like growth factor-II (IGF-II) play a crucial factor in the growth, differentiation and survival of cells in health and disease. IGF-I and IGF-II primarily activate the IGF-I receptor (IGF-IR), which is present on the cell surface. Activation of the IGF-IR stimulates multiple pathways which finally results in multiple biological effects in a variety of tissues and cells. In addition, activation of the IGF-IR has been found to be essential for the growth of cancers. The conventional view in the past was that the IGF-IR was exclusively a tyrosine kinase receptor and that phosphorylation of tyrosine residues, after binding of IGF-I to the IGF-IR, started a cascade of post-receptor events. Recent research has shown that this view was too simplistic. It has been found that the IGF-IR also has kinase-independent functions and may even emit signals in the unoccupied state through some yet-to-be-defined non-canonical pathways. The IGF-IR may further form hybrids with the insulin receptors but also with receptor tyrosine kinases (RTKs) outside the insulin-IGF system. In addition, the IGF-IR has extensive cross-talk with many other receptor tyrosine kinases and their downstream effectors. Moreover, there is now emerging evidence that the IGF-IR utilizes parts of the G-protein coupled receptor (GPCR) pathways: the IGF-IR can be considered as a functional RTK/GPCR hybrid, which integrates the kinase signaling with some IGF-IR mediated canonical GPCR characteristics. Like the classical GPCRs the IGF-IR can also show homologous and heterologous desensitization. Recently, it has been found that after activation by a ligand, the IGF-IR may be translocated into the nucleus and function as a transcriptional cofactor. Thus, in recent years, it has become clear that the IGF-IR signaling pathways are much more complex than first thought. Therefore a big challenge for the (near) future will be how all the new knowledge about IGF-IR signaling can be translated into the clinical practice and improve diagnosis and treatment of diseases.

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Section: The Igf-ir and Endocytosismentioning

confidence: 99%

Section: The Igf-ir and Endocytosismentioning

confidence: 99%

Section: The Igf-ir and Endocytosismentioning

confidence: 99%

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New Insights from IGF-IR Stimulating Activity Analyses: Pathological Considerations

Janssen

2020

Cells

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“…These results can explain why the activated IR is preferentially internalized. IRS1 interacts with the adaptor related protein complex 1 Mu 1 subunit (AP1M1) and AP2M1 through multiple YXXΦ (X, any amino acids; Φ, bulky hydrophobic residues) motifs 46,47 .…”

Section: Irs1/2 Promote Ir Endocytosis Insulin Binding To Ir Promotementioning

confidence: 99%

“…The IRS1-AP2M1 interaction negatively regulates endocytosis of insulin-like growth factor 1 receptor (IGF1R) 47 . We confirmed that in vitro translated Myc-IRS1 full-length and the YXXΦcontaining central region (residues 449-679) bound to GST-AP2M1 ( Fig.…”

Section: Irs1/2 Promote Ir Endocytosis Insulin Binding To Ir Promotementioning

confidence: 99%

Mitotic Regulators and the SHP2-MAPK Pathway Promote Insulin Receptor Endocytosis and Feedback Regulation of Insulin Signaling

Choi¹,

Kikuchi

Gao

et al. 2018

Preprint

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Insulin controls glucose homeostasis and cell growth through bifurcated signaling pathways.Dysregulation of insulin signaling is linked to diabetes and cancer. The spindle checkpoint controls the fidelity of chromosome segregation during mitosis. Here, we show that insulin receptor substrate 1 and 2 (IRS1/2) cooperate with spindle checkpoint proteins to promote insulin receptor (IR) endocytosis through recruiting the clathrin adaptor complex AP2 to IR.A phosphorylation switch of IRS1/2 orchestrated by extracellularly regulated kinase 1 and 2 (ERK1/2) and Src homology phosphatase 2 (SHP2) ensures selective internalization of activated IR. SHP2 inhibition blocks this feedback regulation and growth-promoting IR signaling, prolongs insulin action on metabolism, and improves insulin sensitivity in mice.We propose that mitotic regulators and SHP2 promote feedback inhibition of IR, thereby limiting the duration of insulin signaling. Targeting this feedback inhibition can improve insulin sensitivity.

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Aptamer‐SH2 superbinder‐based targeted therapy for pancreatic ductal adenocarcinoma

Liu

Zhou

et al. 2021

Clinical & Translational Med

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Schematic diagram of XQ-2d-His-SH2 CM-(Arg)9 in PDAC cells and PSCs. XQ-2d-His-SH2 CM-(Arg)9 could bind and penetrate into PSCs, inactivate PSCs, and decrease ECM secretion. XQ-2d-His-SH2 CM-(Arg)9 could reach tumor tissues, recognize, and enter into the PDAC cells. XQ-2d-His-SH2 CM-(Arg)9 could function as a broad-spectrum inhibitor via capturing pY-containing proteins and blocking multitude pY-based signaling pathways in PDAC cells.

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IRS-1 acts as an endocytic regulator of IGF-I receptor to facilitate sustained IGF signaling

Cited by 45 publications

References 80 publications

New Insights from IGF-IR Stimulating Activity Analyses: Pathological Considerations

New Insights from IGF-IR Stimulating Activity Analyses: Pathological Considerations

Mitotic Regulators and the SHP2-MAPK Pathway Promote Insulin Receptor Endocytosis and Feedback Regulation of Insulin Signaling

Aptamer‐SH2 superbinder‐based targeted therapy for pancreatic ductal adenocarcinoma

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