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The reciprocal regulation of gamma-synuclein and IGF-I receptor expression creates a circuit that modulates IGF-I signaling.

ABSTRACT: Insulin-like growth factor (IGF) system plays important roles in carcinogenesis and maintenance of the malignant phenotype. Signaling through the IGF-I receptor (IGF-IR) has been shown to stimulate the growth and motility of a wide range of cancer cells. ?-synuclein (SNCG) is primarily expressed in peripheral neurons but also overexpressed in various cancer cells. Overexpression of SNCG correlates with tumor progression. In the present study we demonstrated a reciprocal regulation of IGF-I signaling and SNCG expression. IGF-I induced SNCG expression in various cancer cells. IGF-IR knockdown or IGF-IR inhibitor repressed SNCG expression. Both phosphatidylinositol 3-kinase and mitogen-activated protein kinase were involved in IGF-I induction of SNCG expression. Interestingly, SNCG knockdown led to proteasomal degradation of IGF-IR, thereby decreasing the steady-state levels of IGF-IR. Silencing of SNCG resulted in a decrease in ligand-induced phosphorylation of IGF-IR and its downstream signaling components, including insulin receptor substrate (IRS), Akt, and ERK1/2. Strikingly, SNCG physically interacted with IGF-IR and IRS-2. Silencing of IRS-2 impaired the interaction between SNCG and IGF-IR. Finally, SNCG knockdown suppressed IGF-I-induced cell proliferation and migration. These data reveal that SNCG and IGF-IR are mutually regulated by each other. SNCG blockade may suppress IGF-I-induced cell proliferation and migration. Conversely, IGF-IR inhibitors may be of utility in suppressing the aberrant expression of SNCG in cancer cells and thereby block its pro-tumor effects.

SUBMITTER: Li M

PROVIDER: S-EPMC2945541 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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The reciprocal regulation of gamma-synuclein and IGF-I receptor expression creates a circuit that modulates IGF-I signaling.

Li Minjing M Yin Yancun Y Hua Hui H Sun Xiangming X Luo Ting T Wang Jiao J Jiang Yangfu Y

The Journal of biological chemistry 20100729 40

Insulin-like growth factor (IGF) system plays important roles in carcinogenesis and maintenance of the malignant phenotype. Signaling through the IGF-I receptor (IGF-IR) has been shown to stimulate the growth and motility of a wide range of cancer cells. γ-synuclein (SNCG) is primarily expressed in peripheral neurons but also overexpressed in various cancer cells. Overexpression of SNCG correlates with tumor progression. In the present study we demonstrated a reciprocal regulation of IGF-I signa ...[more]

PMID: 20670935

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The reciprocal regulation of gamma-synuclein and IGF-I receptor expression creates a circuit that modulates IGF-I signaling.

Publications

The reciprocal regulation of gamma-synuclein and IGF-I receptor expression creates a circuit that modulates IGF-I signaling.

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