An Integrin Binding-defective Mutant of Insulin-like Growth Factor-1 (R36E/R37E IGF1) Acts as a Dominant-negative Antagonist of the IGF1 Receptor (IGF1R) and Suppresses Tumorigenesis but Still Binds to IGF1R

Fujita, Masaaki; Ieguchi, Katsuaki; Cedano-Prieto, Dora; Fong, Andrew Z. C.; Wilkerson, Charles; Chen, Jane Q.; Wu, Mac; Lo, Su Hao; Cheung, Anthony; Wilson, Machelle; Cardiff, Robert D.; Borowsky, Alexander D.; Takada, Yoko; Takada, Yoshikazu

doi:10.1074/jbc.m113.470872

Cited by 36 publications

(36 citation statements)

References 26 publications

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“…We do not, however, observe any association of the chimeric cytoplasmic domain of β 1 integrins with IGF-IR; thus, further analysis is necessary to identify the domains that mediate this interaction. It should be stressed that IGF-1 has been reported to directly bind to integrins and induce the formation of a ternary complex containing integrin-IGF1-IGF-IR [42], [43]. The authors report that an integrin-binding-defective mutant of IGF-1 (R36E/R37E IGF-1), which still binds IGF-IR, acts as a dominant-negative antagonist of IGF-IR and suppresses tumorigenesis; they also show that IGF-1 binds to α 6 β 4 as well as to β 1 integrins, consistent with our data.…”

Section: Discussionmentioning

confidence: 99%

IGF-IR Promotes Prostate Cancer Growth by Stabilizing α5β1 Integrin Protein Levels

et al. 2013

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Dynamic crosstalk between growth factor receptors, cell adhesion molecules and extracellular matrix is essential for cancer cell migration and invasion. Integrins are transmembrane receptors that bind extracellular matrix proteins and enable cell adhesion and cytoskeletal organization. They also mediate signal transduction to regulate cell proliferation and survival. The type 1 insulin-like growth factor receptor (IGF-IR) mediates tumor cell growth, adhesion and inhibition of apoptosis in several types of cancer. We have previously demonstrated that β1 integrins regulate anchorage-independent growth of prostate cancer (PrCa) cells by regulating IGF-IR expression and androgen receptor-mediated transcriptional functions. Furthermore, we have recently reported that IGF-IR regulates the expression of β1 integrins in PrCa cells. We have dissected the mechanism through which IGF-IR regulates β1 integrin expression in PrCa. Here we report that IGF-IR is crucial for PrCa cell growth and that β1 integrins contribute to the regulation of proliferation by IGF-IR. We demonstrate that β1 integrin regulation by IGF-IR does not occur at the mRNA level. Exogenous expression of a CD4 - β1 integrin cytoplasmic domain chimera does not interfere with such regulation and fails to stabilize β1 integrin expression in the absence of IGF-IR. This appears to be due to the lack of interaction between the β1 cytoplasmic domain and IGF-IR. We demonstrate that IGF-IR stabilizes the β1 subunit by protecting it from proteasomal degradation. The α5 subunit, one of the binding partners of β1, is also downregulated along with β1 upon IGF-IR knockdown while no change is observed in the expression of the α2, α3, α4, α6 and α7 subunits. Our results reveal a crucial mechanistic role for the α5β1 integrin, downstream of IGF-IR, in regulating cancer growth.

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Section: Discussionmentioning

confidence: 99%

IGF-IR Promotes Prostate Cancer Growth by Stabilizing α5β1 Integrin Protein Levels

et al. 2013

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“…We found that excess R36E/R37E suppresses the binding of labeled-WT IGF1 to the cell surface [28], and suppresses ternary complex formation induced by WT IGF1 [28]. This demonstrates that R36E/R37E competes with WT IGF1 for the binding to IGF1R on the cell surface.…”

Section: The R36e/r37e Igf1 Mutant Suppresses Cell Proliferation Ancmentioning

confidence: 98%

Crosstalk between insulin-like growth factor (IGF) receptor and integrins through direct integrin binding to IGF1

Takada

Fujita

2017

Cytokine & Growth Factor Reviews

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It has been generally accepted that integrin cell adhesion receptors are involved in growth factor signaling (integrin-growth factor crosstalk), since antagonists to integrins often suppress growth factor signaling. Partly because integrins have been originally identified as cell adhesion receptors to extracellular matrix (ECM) proteins, current models of the crosstalk between IGF1 and integrins propose that ECM ligands (e.g., vitronectin) bind to integrins and IGF1 binds to IGF receptor type 1 (IGF1R), and two separate signals merge inside the cells. Our research proves otherwise. We discovered that IGF1 interacts directly with integrins, and induces integrin-IGF-IGF1R complex formation on the cell surface. IGF1 signaling can be detected in the absence of ECM (anchorage-independent conditions). Integrin antagonists block both ECM-integrin interaction and IGF-integrin interaction, and do not distinguish the two. This is one possible reason why integrin-IGF1 interaction has not been detected. With these new discoveries, we believe that the direct IGF-integrin interaction should be incorporated into models of IGF1 signaling. The integrin-binding defective mutant of IGF1 is defective in inducing IGF signaling, although the mutant still binds to IGF1R. Notably, the IGF1 mutant is dominant-negative and suppresses cell proliferation induced by wt IGF1, and suppresses tumorigenesis in vivo, and thus the IGF1 mutant has potential as a therapeutic.

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“…Despite the opposing results, integrins are still attractive target molecules for an inhibition of tumor growth because integrins cooperate with some growth factor receptor signals for cell proliferation . Therefore, many researchers devote their intensive works to the development of anti‐integrin drugs . EphA1 interacted with fibronectin type I repeat and integrin‐linked kinase (ILK) mediated by the extracellular and intracellular domain of EphA1, respectively .…”

Section: The Signaling Crosstalk Among Integrin Ecm and Epha1mentioning

confidence: 99%

Roles of EphA1/A2 and ephrin‐A1 in cancer

Ieguchi

Maru

2019

Cancer Science

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The biological functions of the Eph/ephrin system have been intensively investigated and well documented so far since its discovery in 1987. Although the Eph/ephrin system has been implicated in pathological settings such as Alzheimer's disease and cancer, the molecular mechanism of the Eph/ephrin system in those diseases is not well understood. Especially in cancer, recent studies have demonstrated that most of Eph and ephrin are up‐ or down‐regulated in various types of cancer, and have been implicated in tumor progression, tumor malignancy, and prognosis. However, they lack consistency and are in controversy. The localization patterns of EphA1 and EphA2 in mouse lungs are very similar, and both knockout mice showed similar phenotypes in the lungs. Ephrin‐A1 that is a membrane‐anchored ligand for EphAs was co‐localized with EphA1 and EphA2 in lung vascular endothelial cells. We recently uncovered the molecular mechanism of ephrin‐A1‐induced lung metastasis by understanding the physiological function of ephrin‐A1 in lungs. This review focuses on the function of EphA1, EphA2, and ephrin‐A1 in tumors and an establishment of pre‐metastatic microenvironment in the lungs.

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An Integrin Binding-defective Mutant of Insulin-like Growth Factor-1 (R36E/R37E IGF1) Acts as a Dominant-negative Antagonist of the IGF1 Receptor (IGF1R) and Suppresses Tumorigenesis but Still Binds to IGF1R

Cited by 36 publications

References 26 publications

IGF-IR Promotes Prostate Cancer Growth by Stabilizing α5β1 Integrin Protein Levels

IGF-IR Promotes Prostate Cancer Growth by Stabilizing α5β1 Integrin Protein Levels

Crosstalk between insulin-like growth factor (IGF) receptor and integrins through direct integrin binding to IGF1

Roles of EphA1/A2 and ephrin‐A1 in cancer

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