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The Cdc42-interacting protein-4 (CIP4) gene knock-out mouse reveals delayed and decreased endocytosis
Yanming Feng1, Sean M Hartig, John E Bechill
1Division of Pediatrics, University of Texas, MD Anderson Cancer Center, Houston, Texas 77030, USA.
Abstract:
The newly described F-BAR (Fer/CIP4 and Bin, amphiphysin, Rvs) family of proteins includes Cdc42-interacting protein-4 (CIP4), formin-binding protein-17 (FBP-17) and transactivator of cytoskeletal assembly-1 (Toca-1), and drives membrane deformation and invagination. Membrane remodeling affects endocytosis, vesicle budding, and cargo selection. The F-BAR family presents a novel family of proteins, which little is known about their in vivo function. We investigated the physiological role of CIP4, by creating Cip4-null mice through homologous recombination. Compared with their wild-type littermates, the Cip4-null mice displayed lower early post-prandial glucose levels. Adipocytes isolated from Cip4-null mice exhibited increased [(14)C]2-deoxyglucose uptake compared with cells from wild-type mice. The enhanced insulin sensitivity was not due to higher levels of insulin or phospho-Akt, a critical player in insulin signaling. However, higher glucose transporter 4 (GLUT4) levels were detected in muscle membrane fractions in Cip4-null mice under insulin stimulation. Mouse embryonic fibroblasts from Cip4-null mice demonstrated decreased transferrin uptake, fluorescein isothiocyanate-dextran, and horseradish peroxidase uptake, indicating that CIP4 affects multiple modes of endocytosis. These studies demonstrate a physiological role for CIP4 in endocytosis leading to a whole animal phenotype.
Insights
Cdc42-interacting protein-4 (CIP4) influences glucose metabolism and insulin sensitivity. Mice lacking CIP4 show enhanced glucose uptake and altered endocytosis, revealing its physiological role in whole-body function.
Area of Science:
- Cell Biology
- Molecular Biology
- Physiology
Background:
- The F-BAR protein family, including Cdc42-interacting protein-4 (CIP4), is involved in membrane remodeling processes like endocytosis.
- The in vivo functions of the F-BAR protein family, particularly CIP4, remain largely uncharacterized.
Purpose of the Study:
- To investigate the physiological role of CIP4 in vivo.
- To determine the impact of CIP4 deficiency on glucose metabolism and endocytosis.
Main Methods:
- Generation of Cip4-null mice using homologous recombination.
- Assessment of glucose levels and insulin sensitivity in knockout and wild-type mice.
- Analysis of glucose uptake in isolated adipocytes and endocytosis in mouse embryonic fibroblasts.
Main Results:
- Cip4-null mice exhibited lower post-prandial glucose levels and increased insulin sensitivity.
- Enhanced glucose uptake in adipocytes from Cip4-null mice was associated with increased GLUT4 levels in muscle membranes.
- Impaired endocytosis of transferrin, dextran, and horseradish peroxidase was observed in fibroblasts from Cip4-null mice.
Conclusions:
- CIP4 plays a significant physiological role in regulating glucose metabolism and insulin sensitivity.
- CIP4 is involved in multiple modes of endocytosis, impacting cellular and whole-animal phenotypes.
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