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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 draws of IGF-IR regulation by various ligases and adaptors. Upon ligand-stimulation ubiquitin ligases complex with the IGF-IR either directly or through adaptor proteins, promoting receptor ubiquitination, internalization, and sorting for degradation.
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Figure 1: Schematic draws of IGF-IR regulation by various ligases and adaptors. Upon ligand-stimulation ubiquitin ligases complex with the IGF-IR either directly or through adaptor proteins, promoting receptor ubiquitination, internalization, and sorting for degradation.

Mentions: The IGF receptor I (IGF-IR) and its cognate ligands insulin-like growth factors I and II (IGF-I and IGF-II) play an essential role in modulating mammalian growth in vitro (1, 2) and in vivo (3–5). The IGF-IR, IGF-I, and IGF-II are often deregulated in cancer and may have a critical function not only in the early phases of tumor initiation but also in cancer progression and resistance to therapies (6–9). IGF-II, and to a lesser extent IGF-I, binds to the isoform A of the insulin receptor (IR-A), which has high homology to the IGF-IR (10, 11) (Figure 1). The IR-A is the fetal form of the IR and mediates primarily mitogenesis upon IGF-II or insulin activation (11–13) and is also implicated in transformation (14, 15), while the second IR isoform (IR-B) is involved in glucose homeostasis of insulin-sensitive organs (11, 14). Prevalent expression of the IR-A over the IR-B has been discovered in several cancer models, and an autocrine proliferative loop between IGF-II and the IR-A has been detected in malignant thyrocytes, breast cancer, and sarcoma cells (16–19).


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 draws of IGF-IR regulation by various ligases and adaptors. Upon ligand-stimulation ubiquitin ligases complex with the IGF-IR either directly or through adaptor proteins, promoting receptor ubiquitination, internalization, and sorting for degradation.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Schematic draws of IGF-IR regulation by various ligases and adaptors. Upon ligand-stimulation ubiquitin ligases complex with the IGF-IR either directly or through adaptor proteins, promoting receptor ubiquitination, internalization, and sorting for degradation.
Mentions: The IGF receptor I (IGF-IR) and its cognate ligands insulin-like growth factors I and II (IGF-I and IGF-II) play an essential role in modulating mammalian growth in vitro (1, 2) and in vivo (3–5). The IGF-IR, IGF-I, and IGF-II are often deregulated in cancer and may have a critical function not only in the early phases of tumor initiation but also in cancer progression and resistance to therapies (6–9). IGF-II, and to a lesser extent IGF-I, binds to the isoform A of the insulin receptor (IR-A), which has high homology to the IGF-IR (10, 11) (Figure 1). The IR-A is the fetal form of the IR and mediates primarily mitogenesis upon IGF-II or insulin activation (11–13) and is also implicated in transformation (14, 15), while the second IR isoform (IR-B) is involved in glucose homeostasis of insulin-sensitive organs (11, 14). Prevalent expression of the IR-A over the IR-B has been discovered in several cancer models, and an autocrine proliferative loop between IGF-II and the IR-A has been detected in malignant thyrocytes, breast cancer, and sarcoma cells (16–19).

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