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Ligand-mediated endocytosis and trafficking of the insulin-like growth factor receptor I and insulin receptor modulate receptor function.

Morcavallo A, Stefanello M, Iozzo RV, Belfiore A, Morrione A - Front Endocrinol (Lausanne) (2014)

Bottom Line: Ligand-mediated endocytosis of tyrosine-kinases receptors plays a critical role in modulating the duration and intensity of receptors action but while the signaling pathways induced by the IGF-IR and IR are quite characterized, very little is still known about the mechanisms and proteins that regulate ligand-induced IGF-IR and IR endocytosis and trafficking.In addition, how these processes affect receptor downstream signaling has not been fully characterized.Here, we discuss the current understanding of the mechanisms and proteins regulating IGF-IR and IR endocytosis and sorting and their implications in modulating ligand-induced biological responses.

View Article: PubMed Central - PubMed

Affiliation: Departments of Urology, Sydney Kimmel Cancer Center, Thomas Jefferson University , Philadelphia, PA , USA ; Department of Health Sciences and Endocrinology, University Magna Graecia of Catanzaro , Catanzaro , Italy.

ABSTRACT
The insulin-like growth factor system and its two major receptors, the IGF receptor I (IGF-IR) and IR, plays a central role in a variety of physiological cellular processes including growth, differentiation, motility, and glucose homeostasis. The IGF-IR is also essential for tumorigenesis through its capacity to protect cancer cells from apoptosis. The IR is expressed in two isoforms: the IR isoform A (IR-A) and isoform B (IR-B). While the role of the IR-B in the regulation of metabolic effects has been known for several years, more recent evidence suggests that the IR, and in particular the IR-A, may be involved in the pathogenesis of cancer. Ligand-mediated endocytosis of tyrosine-kinases receptors plays a critical role in modulating the duration and intensity of receptors action but while the signaling pathways induced by the IGF-IR and IR are quite characterized, very little is still known about the mechanisms and proteins that regulate ligand-induced IGF-IR and IR endocytosis and trafficking. In addition, how these processes affect receptor downstream signaling has not been fully characterized. Here, we discuss the current understanding of the mechanisms and proteins regulating IGF-IR and IR endocytosis and sorting and their implications in modulating ligand-induced biological responses.

No MeSH data available.


Related in: MedlinePlus

Schematic diagram of pathways regulating endocytosis. The IGF-IR and the IR are internalized in ligand-dependent manner through both clathrin-dependent and -independent pathways, sorted into early endosomes and either targeted for degradation in the lysosomes or recycled to the cell surface.
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Figure 2: Schematic diagram of pathways regulating endocytosis. The IGF-IR and the IR are internalized in ligand-dependent manner through both clathrin-dependent and -independent pathways, sorted into early endosomes and either targeted for degradation in the lysosomes or recycled to the cell surface.

Mentions: Because IGF-II is mitogenic through the IR-A at a comparable rate if not even higher than insulin, in spite of an affinity for the IR-A 3–5-fold lower than insulin and a reduced ability to promote receptor phosphorylation and activation of downstream effectors (11, 12), we undertook studies to test the hypothesis that insulin and IGF-II could affect biological responses by differentially regulating IR-A endocytosis and trafficking. Taking advantage of the unique model of R−/IR-A cells, which lack the IGF-IR (53) and were engineered to express solely the IR-A (54), we demonstrated that insulin and IGF-II considerably differ in their ability to regulate IR-A and downstream effectors trafficking and stability (55). Indeed, insulin stimulation of R−/IR-A cells promoted IR-A internalization, which was instead only modestly affected by IGF-II stimulation. Significantly, the difference in internalization was not due to IR-A ubiquitination, which was comparable in IGF-II and insulin-stimulated R−/IR-A cells (55). As control, we used the insulin analog NMeTyrB26-insulin, which has lower affinity than insulin for IR-A, and demonstrated that it promoted IR-A phosphorylation, internalization, and proliferation at a rate comparable to IGF-II. More importantly, we discovered that prolonged stimulation of R−/IR-A cells with insulin, but not with IGF-II or NMeTyrB26-insulin, targeted the IR-A and IRS-1 for degradation (55). We also elucidated the pathways of IR-A endocytosis and sorting and showed that upon insulin or IGF-II stimulation, the IR-A was internalized through clathrin-dependent and independent pathways, but only the clathrin-dependent internalization was required for IR-A degradation (55) (Figure 2). These findings provide a mechanistic explanation to previous studies showing that, in cells expressing only the IR-A isoform, insulin, and IGF-II induce partially different gene expression (56), downstream signaling (57), and involvement of different substrates (58).


Ligand-mediated endocytosis and trafficking of the insulin-like growth factor receptor I and insulin receptor modulate receptor function.

Morcavallo A, Stefanello M, Iozzo RV, Belfiore A, Morrione A - Front Endocrinol (Lausanne) (2014)

Schematic diagram of pathways regulating endocytosis. The IGF-IR and the IR are internalized in ligand-dependent manner through both clathrin-dependent and -independent pathways, sorted into early endosomes and either targeted for degradation in the lysosomes or recycled to the cell surface.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4269189&req=5

Figure 2: Schematic diagram of pathways regulating endocytosis. The IGF-IR and the IR are internalized in ligand-dependent manner through both clathrin-dependent and -independent pathways, sorted into early endosomes and either targeted for degradation in the lysosomes or recycled to the cell surface.
Mentions: Because IGF-II is mitogenic through the IR-A at a comparable rate if not even higher than insulin, in spite of an affinity for the IR-A 3–5-fold lower than insulin and a reduced ability to promote receptor phosphorylation and activation of downstream effectors (11, 12), we undertook studies to test the hypothesis that insulin and IGF-II could affect biological responses by differentially regulating IR-A endocytosis and trafficking. Taking advantage of the unique model of R−/IR-A cells, which lack the IGF-IR (53) and were engineered to express solely the IR-A (54), we demonstrated that insulin and IGF-II considerably differ in their ability to regulate IR-A and downstream effectors trafficking and stability (55). Indeed, insulin stimulation of R−/IR-A cells promoted IR-A internalization, which was instead only modestly affected by IGF-II stimulation. Significantly, the difference in internalization was not due to IR-A ubiquitination, which was comparable in IGF-II and insulin-stimulated R−/IR-A cells (55). As control, we used the insulin analog NMeTyrB26-insulin, which has lower affinity than insulin for IR-A, and demonstrated that it promoted IR-A phosphorylation, internalization, and proliferation at a rate comparable to IGF-II. More importantly, we discovered that prolonged stimulation of R−/IR-A cells with insulin, but not with IGF-II or NMeTyrB26-insulin, targeted the IR-A and IRS-1 for degradation (55). We also elucidated the pathways of IR-A endocytosis and sorting and showed that upon insulin or IGF-II stimulation, the IR-A was internalized through clathrin-dependent and independent pathways, but only the clathrin-dependent internalization was required for IR-A degradation (55) (Figure 2). These findings provide a mechanistic explanation to previous studies showing that, in cells expressing only the IR-A isoform, insulin, and IGF-II induce partially different gene expression (56), downstream signaling (57), and involvement of different substrates (58).

Bottom Line: Ligand-mediated endocytosis of tyrosine-kinases receptors plays a critical role in modulating the duration and intensity of receptors action but while the signaling pathways induced by the IGF-IR and IR are quite characterized, very little is still known about the mechanisms and proteins that regulate ligand-induced IGF-IR and IR endocytosis and trafficking.In addition, how these processes affect receptor downstream signaling has not been fully characterized.Here, we discuss the current understanding of the mechanisms and proteins regulating IGF-IR and IR endocytosis and sorting and their implications in modulating ligand-induced biological responses.

View Article: PubMed Central - PubMed

Affiliation: Departments of Urology, Sydney Kimmel Cancer Center, Thomas Jefferson University , Philadelphia, PA , USA ; Department of Health Sciences and Endocrinology, University Magna Graecia of Catanzaro , Catanzaro , Italy.

ABSTRACT
The insulin-like growth factor system and its two major receptors, the IGF receptor I (IGF-IR) and IR, plays a central role in a variety of physiological cellular processes including growth, differentiation, motility, and glucose homeostasis. The IGF-IR is also essential for tumorigenesis through its capacity to protect cancer cells from apoptosis. The IR is expressed in two isoforms: the IR isoform A (IR-A) and isoform B (IR-B). While the role of the IR-B in the regulation of metabolic effects has been known for several years, more recent evidence suggests that the IR, and in particular the IR-A, may be involved in the pathogenesis of cancer. Ligand-mediated endocytosis of tyrosine-kinases receptors plays a critical role in modulating the duration and intensity of receptors action but while the signaling pathways induced by the IGF-IR and IR are quite characterized, very little is still known about the mechanisms and proteins that regulate ligand-induced IGF-IR and IR endocytosis and trafficking. In addition, how these processes affect receptor downstream signaling has not been fully characterized. Here, we discuss the current understanding of the mechanisms and proteins regulating IGF-IR and IR endocytosis and sorting and their implications in modulating ligand-induced biological responses.

No MeSH data available.


Related in: MedlinePlus