Regulation of actin dynamics by PI(4,5)P2 in cell migration and endocytosis
Open accessAbstract
The actin cytoskeleton is indispensable for several cellular processes, including migration, morphogenesis, polarized growth, endocytosis, and phagocytosis. The organization and dynamics of the actin cytoskeleton in these processes are regulated by Rho family small GTPases and kinase-phosphatase pathways. Moreover, membrane phospholipids, especially the phosphatidylinositol phosphates have emerged as important regulators of actin dynamics. From these, PI(4,5)P 2 is the most abundant at the plasma membrane, and directly regulates the activities and subcellular localizations of numerous actin-binding proteins. Here, we discuss recent studies demonstrating that actin-binding proteins interact with PI(4,5)P 2 -rich membranes through drastically different affinities and dynamics correlating with their roles in cytoskeletal dynamics. Moreover, by using mesenchymal cell migration and clathrin-mediated endocytosis as examples, we present a model for how interplay between PI(4,5)P 2 and actin-binding proteins control the actin cytoskeleton in cells.
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PI(4,5)P2 is a substrate for PLC and PI3K.
“PI(4,5)P2 is a substrate for two signalling pathways.”
From Phosphatidylinositol(4,5)bisphosphate: diverse functions at the plasma membrane (2020) · cites this paper as [14]
PLC hydrolysis of PI(4,5)P2 generates IP3 and DAG.
“Phospholipase C (PLC) leads to the generation of two second messengers, inositol(1,4,5)trisphosphate (I(1,4,5)P3), known trigger for mobilising Ca2+ from endoplasmic reticulum (ER) stores and diacylglycerol (DAG), an activator for protein kinase C (PKC).”
From Phosphatidylinositol(4,5)bisphosphate: diverse functions at the plasma membrane (2020) · cites this paper as [14]
DAG activates PKC.
“Phospholipase C (PLC) leads to the generation of two second messengers, inositol(1,4,5)trisphosphate (I(1,4,5)P3), known trigger for mobilising Ca2+ from endoplasmic reticulum (ER) stores and diacylglycerol (DAG), an activator for protein kinase C (PKC).”
From Phosphatidylinositol(4,5)bisphosphate: diverse functions at the plasma membrane (2020) · cites this paper as [14]
PI3K generates PI(3,4,5)P3, a lipid with wide-ranging functions.
“The second pathway is phosphoinositide-3-kinase (PI3K) to make PI(3,4,5)P3, a lipid with wide-ranging functions.”
From Phosphatidylinositol(4,5)bisphosphate: diverse functions at the plasma membrane (2020) · cites this paper as [14]
IP3 mobilises Ca2+ from ER stores.
“Phospholipase C (PLC) leads to the generation of two second messengers, inositol(1,4,5)trisphosphate (I(1,4,5)P3), known trigger for mobilising Ca2+ from endoplasmic reticulum (ER) stores and diacylglycerol (DAG), an activator for protein kinase C (PKC).”
From Phosphatidylinositol(4,5)bisphosphate: diverse functions at the plasma membrane (2020) · cites this paper as [14]
PI(4,5)P2 is one of the main drivers of actin cytoskeleton remodelling; it interacts with several actin-binding proteins at the plasma membrane and regulates their activity through its levels.
“One of the main drivers for this process is PI(4,5)P2 [87]; it interacts with several actin-binding proteins at the plasma membrane, serving to regulate their activity through its levels (Figure 5) [14,88].”
From Phosphatidylinositol(4,5)bisphosphate: diverse functions at the plasma membrane (2020) · cites this paper as [14]
Cofilin has low affinity for PI(4,5)P2 and is retained at the plasma membrane under resting conditions when PI(4,5)P2 levels are high; when PI(4,5)P2 levels fall, cofilin is released into the cytosol to promote actin filament disassembly.
“Proteins such as cofilin that disassemble actin filaments have low affinity for PI(4,5)P2. Thus cofilin is retained at the plasma membrane under resting conditions when PI(4,5)P2 levels are high. During actin cytoskeletal remodelling, when PI(4,5)P2 levels are locally altered, proteins that aid actin filament disassembly such as cofilin are released into the cytosol where it can engage in disas”
From Phosphatidylinositol(4,5)bisphosphate: diverse functions at the plasma membrane (2020) · cites this paper as [14]
ERM family proteins cross-link actin filaments to the cell cortex; they have very high affinity for PI(4,5)P2 and dissociate from the membrane only under extreme circumstances.
“ERM family proteins serve to securely cross-link actin filaments to the cell cortex; they have a very high affinity for PI(4,5)P2 and only dissociates from the membrane under extreme circumstances [14,91].”
From Phosphatidylinositol(4,5)bisphosphate: diverse functions at the plasma membrane (2020) · cites this paper as [14]
N-WASP has high affinity for PI(4,5)P2 and is activated in regions of high PI(4,5)P2 density, activating Arp2/3 to initiate actin nucleation; this is important for cell migration and N-WASP localises at extending lamellipodia.
“N-WASP has a high affinity for PI(4,5)P2, and is activated in regions with a high PI(4,5)P2 density, which in turn activates the actin-related protein 2/3 (Arp2/3) complex to initiate actin nucleation. This is important for cell migration; N-WASP localise at extending lamellipodia which are regions of high PI(4,5)P2 density.”
From Phosphatidylinositol(4,5)bisphosphate: diverse functions at the plasma membrane (2020) · cites this paper as [14]
Cites
Phosphoinositides in Control of Membrane Dynamics
Schink, K. O., Tan, K.-W., & Stenmark, H. (2016) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-111315-125349 · Cited by 283 · see citing works
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Phosphatidylinositol(4,5)bisphosphate: diverse functions at the plasma membrane
Katan, M., & Cockcroft, S. (2020) · Essays in Biochemistry · doi:10.1042/ebc20200041 · Cited by 176 · see citing works
Intracellular organization in cell polarity—Placing organelles into the polarity loop
Vaidžiulytė, K., Coppey, M., & Schauer, K. (2019) · Journal of Cell Science · doi:10.1242/jcs.230995 · Cited by 31 · see citing works
- Authors
- Senju, Y., & Lappalainen, P.
- Affiliations
- University of Helsinki (FI)
- Corresponding author
- Lappalainen, Pekka
- Venue
- Current Opinion in Cell Biology
- Publisher
- Elsevier BV
- Published
- 2019-02
- Volume
- 56
- Pages
- 7-13
- ISSN
- 0955-0674 (ISSN-L)
- OpenAlex
- W2891655059
- Cited by
- 101
- References
- 1
- Citations by year
- 2026: 8 · 2025: 11 · 2024: 8 · 2023: 10 · 2022: 16 · 2021: 16 · 2020: 19 · 2019: 13
- FWCI
- 1.35
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Locations
- Current Opinion in Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Työväentutkimus Vuosikirja (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Keywords
- phosphatidylinositol 4,5-bisphosphate, phosphoinositides, actin cytoskeleton dynamics, cell migration, clathrin-mediated endocytosis, actin-binding proteins, Rho GTPases, membrane phospholipids, mesenchymal migration, plasma membrane
- MeSH terms
- Actins, Animals, Cell Membrane, Cell Movement, Endocytosis, Microfilament Proteins, Actin Cytoskeleton, Signal Transduction, Phosphatidylinositol Phosphates
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