Nuclear insulin-like growth factor 1 receptor phosphorylates proliferating cell nuclear antigen and rescues stalled replication forks after DNA damage

Waraky, Ahmed; Lin, Yingbo; Warsito, Dudi; Haglund, Felix; Aleem, Eiman; Larsson, Olle

doi:10.1074/jbc.m117.781492

Cited by 31 publications

(30 citation statements)

References 52 publications

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“…Several different mechanisms for the involvement of IGF1R in radioresistance have been proposed. Nuclear IGF1R is known to physically interact with and phosphorylate proliferating cell nuclear antigen (PCNA), a key mediator of the DNA damage response (Waraky et al ., ). A role for IGF1R has been suggested in both of the major pathways for repairing DNA double‐strand breaks, namely homologous recombination and non‐homologous end joining (Chitnis et al ., ).…”

Section: Role Of Igf System In Chemoresistancementioning

confidence: 97%

IGF signalling in germ cells and testicular germ cell tumours: roles and therapeutic approaches

Selfe

Shipley

2019

Andrology

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The insulin‐like growth factor (IGF) axis plays key roles in normal tissue growth and development as well as in the progression of several tumour types and their subsequent growth and progression to a metastatic phenotype. This review explores the role of IGF system in normal germ cell development and function in addition to examining the evidence for deregulation of IGF signalling in cancer, with particular relevance to evidence supporting a role in testicular germ cell tumours (TGCTs). Despite the clear preclinical rationale for targeting the IGF axis in cancer, there has been a lack of progress in identifying which patients may benefit from such therapy. Future employment of agents targeting the IGF pathway is expected to concentrate on their use in combination with other treatments to prevent resistance and exploit their potential as chemo‐ and radiosensitizers.

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Section: Role Of Igf System In Chemoresistancementioning

confidence: 97%

IGF signalling in germ cells and testicular germ cell tumours: roles and therapeutic approaches

Selfe

Shipley

2019

Andrology

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“…They further showed that translocation to the nucleus was mediated by SUMOylation of IGF-1R by the SUMO modifier SUMO-1. It has since been shown that nuclear IGF-1R interacts with several different nuclear proteins and functions to regulate the cell cycle, DNA damage responses, invasion, and metastasis (26)(27)(28)(29).…”

Section: Intracellular Igf-1r Insr and Hybrid-rmentioning

confidence: 99%

The IGF/Insulin-IGFBP Axis in Corneal Development, Wound Healing, and Disease

2020

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The insulin-like growth factor (IGF) family plays key roles in growth and development. In the cornea, IGF family members have been implicated in proliferation, differentiation, and migration, critical events that maintain a smooth refracting surface that is essential for vision. The IGF family is composed of multiple ligands, receptors, and ligand binding proteins. Expression of IGF type 1 receptor (IGF-1R), IGF type 2 receptor (IGF-2R), and insulin receptor (INSR) in the cornea has been well characterized, including the presence of the IGF-1R and INSR hybrid (Hybrid-R) in the corneal epithelium. Recent data also indicates that each of these receptors display unique intracellular localization. Thus, in addition to canonical ligand binding at the plasma membrane and the initiation of downstream signaling cascades, IGF-1R, INSR, and Hybrid-R also function to regulate mitochondrial stability and nuclear gene expression. IGF-1 and IGF-2, two of three principal ligands, are polypeptide growth factors that function in all cellular layers of the cornea. Unlike IGF-1 and IGF-2, the hormone insulin plays a unique role in the cornea, different from many other tissues in the body. In the corneal epithelium, insulin is not required for glucose uptake, due to constitutive activation of the glucose transporter, GLUT1. However, insulin is needed for the regulation of metabolism, circadian rhythm, autophagy, proliferation, and migration after wounding. There is conflicting evidence regarding expression of the six IGF-binding proteins (IGFBPs), which function primarily to sequester IGF ligands. Within the cornea, IGFBP-2 and IGFBP-3 have identified roles in tissue homeostasis. While IGFBP-3 regulates growth control and intracellular receptor localization in the corneal epithelium, both IGFBP-2 and IGFBP-3 function in corneal fibroblast differentiation and myofibroblast proliferation, key events in stromal wound healing. IGFBP-2 has also been linked to cellular overgrowth in pterygium. There is a clear role for IGF family members in regulating tissue homeostasis in the cornea. This review summarizes what is known regarding the function of IGF and related proteins in corneal development, during wound healing, and in the pathophysiology of disease. Finally, we highlight key areas of research that are in need of future study.

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“…Mass spectrometry analyses identified 13 phosphorylation sites on PCNA, of which Y211 and S261 seem to be most prevalent [ 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 ] ( Figure 7 and Supplementary Table S1 ). Phosphorylation of PCNA on Y211 by the epidermal growth factor receptor (EGFR) enhances the stability of chromatin-bound PCNA but also weakens its interaction with mismatch repair proteins and thus suppresses the mismatch repair pathway [ 134 , 135 ] ( Figure 8 ).…”

Section: Post-translational Modifications Of Proliferating Cell Numentioning

confidence: 99%

“…Phosphorylation of PCNA on Y211 by the epidermal growth factor receptor (EGFR) enhances the stability of chromatin-bound PCNA but also weakens its interaction with mismatch repair proteins and thus suppresses the mismatch repair pathway [ 134 , 135 ] ( Figure 8 ). Furthermore, a crosstalk between phosphorylation and ubiquitination seems to be important for replication stress response in light of the recent findings that phosphorylation of Y60, Y133 and Y250 by IGF-1R promotes PCNA ubiquitination and replication fork restart after UV or MMS exposure [ 131 ].…”

Section: Post-translational Modifications Of Proliferating Cell Numentioning

confidence: 99%

“…Pol η has two more internal PIP-boxes, which do now show binding to PCNA in vitro, but are important for PCNA monoubiquitination and stimulation of Pol η polymerase activity by PCNA [ 58 ]. PTMs were extracted from high-throughput mass spectrometry studies or low-throughput functional studies [ 69 , 71 , 76 , 78 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 142 , 143 , 144 , 145 , 146 , 147 , 148 , 149 , 150 , 1...…”

Section: Figurementioning

confidence: 99%

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Maneuvers on PCNA Rings during DNA Replication and Repair

Slade

2018

Genes

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DNA replication and repair are essential cellular processes that ensure genome duplication and safeguard the genome from deleterious mutations. Both processes utilize an abundance of enzymatic functions that need to be tightly regulated to ensure dynamic exchange of DNA replication and repair factors. Proliferating cell nuclear antigen (PCNA) is the major coordinator of faithful and processive replication and DNA repair at replication forks. Post-translational modifications of PCNA, ubiquitination and acetylation in particular, regulate the dynamics of PCNA-protein interactions. Proliferating cell nuclear antigen (PCNA) monoubiquitination elicits ‘polymerase switching’, whereby stalled replicative polymerase is replaced with a specialized polymerase, while PCNA acetylation may reduce the processivity of replicative polymerases to promote homologous recombination-dependent repair. While regulatory functions of PCNA ubiquitination and acetylation have been well established, the regulation of PCNA-binding proteins remains underexplored. Considering the vast number of PCNA-binding proteins, many of which have similar PCNA binding affinities, the question arises as to the regulation of the strength and sequence of their binding to PCNA. Here I provide an overview of post-translational modifications on both PCNA and PCNA-interacting proteins and discuss their relevance for the regulation of the dynamic processes of DNA replication and repair.

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Nuclear insulin-like growth factor 1 receptor phosphorylates proliferating cell nuclear antigen and rescues stalled replication forks after DNA damage

Cited by 31 publications

References 52 publications

IGF signalling in germ cells and testicular germ cell tumours: roles and therapeutic approaches

IGF signalling in germ cells and testicular germ cell tumours: roles and therapeutic approaches

The IGF/Insulin-IGFBP Axis in Corneal Development, Wound Healing, and Disease

Maneuvers on PCNA Rings during DNA Replication and Repair

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