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PI3Kβ is selectively required for growth factor-stimulated macropinocytosis
Gilbert Salloum1, Charles T Jakubik2, Zahra Erami1
1Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Abstract:
Macropinocytosis is an actin-dependent but clathrin-independent endocytic process by which cells nonselectively take up large aliquots of extracellular material. Macropinocytosis is used for immune surveillance by dendritic cells, as a route of infection by viruses and protozoa, and as a nutrient uptake pathway in tumor cells. In this study, we explore the role of class I phosphoinositide 3-kinases (PI3Ks) during ligand-stimulated macropinocytosis. We find that macropinocytosis in response to receptor tyrosine kinase activation is strikingly dependent on a single class I PI3K isoform, namely PI3Kβ (containing the p110β catalytic subunit encoded by PIK3CB). Loss of PI3Kβ expression or activity blocks macropinocytosis at early steps, before the formation of circular dorsal ruffles, but also plays a role in later steps, downstream from Rac1 activation. PI3Kβ is also required for the elevated levels of constitutive macropinocytosis found in tumor cells that are defective for the PTEN tumor suppressor. Our data shed new light on PI3K signaling during macropinocytosis, and suggest new therapeutic uses for pharmacological inhibitors of PI3Kβ.
Insights
Class I phosphoinositide 3-kinases (PI3Ks) are crucial for macropinocytosis. This study reveals PI3Kβ is essential for both normal and tumor cell macropinocytosis, suggesting PI3Kβ inhibitors as potential therapeutics.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Biology
Background:
- Macropinocytosis is a non-selective cellular uptake process vital for immune surveillance, pathogen entry, and nutrient acquisition in tumors.
- Class I phosphoinositide 3-kinases (PI3Ks) are key regulators of cellular signaling pathways, including endocytosis.
Purpose of the Study:
- To investigate the specific role of class I PI3K isoforms in ligand-stimulated macropinocytosis.
- To elucidate the involvement of PI3Kβ in both normal and tumor cell macropinocytosis.
Main Methods:
- Utilized genetic manipulation to assess the impact of PI3Kβ loss on macropinocytosis.
- Investigated PI3Kβ's role in relation to receptor tyrosine kinase activation and Rac1 signaling.
- Examined PI3Kβ function in tumor cells with PTEN deficiency.
Main Results:
- Macropinocytosis is highly dependent on the PI3Kβ isoform (encoded by PIK3CB) upon receptor tyrosine kinase activation.
- Loss of PI3Kβ function impairs macropinocytosis at early stages and also affects later steps downstream of Rac1.
- PI3Kβ is indispensable for the heightened constitutive macropinocytosis observed in PTEN-deficient tumor cells.
Conclusions:
- PI3Kβ plays a critical and multifaceted role in regulating macropinocytosis.
- Targeting PI3Kβ with pharmacological inhibitors may offer novel therapeutic strategies for cancer treatment.
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