PIP2 and Talin Join Forces to Activate Integrin

Orłowski, Adam; Kukkurainen, Sampo; Pöyry, Annika; Rissanen, Sami; Vattulainen, Ilpo; Hytönen, Vesa P.; Róg, Tomasz

doi:10.1021/acs.jpcb.5b06457

Cited by 27 publications

(29 citation statements)

References 69 publications

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“…These localized PI(4,5)P 2 pools have been hypothesized to play a major role in mediating actin polymerization by affecting actin-capping proteins and by mediating the directionality of actin polymerization along the extracellular migration by interacting with talin and vinculin [3,11,12]. This interaction between PI(4,5)P 2 and talin also mediates the activation and the function of integrins [42], including the formation of talin-integrin clusters [43]. We observe talin and several focal adhesion proteins bind to IQGAP1 (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…IQGAP1 has been found to form complexes with Cdc42, Guanine Nucleotide exchange factor FGD6, the Rho GTPase-activating protein ARHGAP10, filamin and talin close to focal adhesions [41]. Talin-PI(4,5)P 2 mediate the activation and the function of integrins [42], including the formation of talin-integrin clusters [43]. eGFP-IQGAP1 strongly binds to mCherry-talin in HeLa cells when quantified by FLIM-FRET and is slightly enhanced by EGF stimulation (Fig.…”

Section: Iqgap1 Regulates β-Actin Complex Formation In Response To Prmentioning

confidence: 99%

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IQGAP1 connects phosphoinositide signaling to cytoskeletal reorganization

Yerramilli

Ross

Lindberg³

et al. 2019

Preprint

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IQGAP1 is a multi-domain protein that acts as a scaffold for multiple signaling pathways. IQGAP1 generates the lipid messenger PI(3,4,5)P 3 by scaffolding the phosphoinositide kinases PIPKIs and PI3K.The dynamics of this scaffolding protein complex in intact, living cells are unknown. Here, we delineate the role of IQGAP1 in PI(3,4,5)P 3 -mediated signaling in live cells under basal and stimulated conditions using fluorescence lifetime imaging microscopy. We demonstrate that IQGAP1 interacts strongly with PIPKIγ at intracellular entities and on the plasma membrane, and scaffolds PI3K and PIPKIγ in response to physiological changes. Additionally, we show that IQGAP1 scaffolds phosphoinositides with PI3K, PIPKIγ and EGFR, and forms clusters upon cell stimulation with epidermal growth factor. Importantly, we show that IQGAP1 connects PI(3,4,5)P 3 -mediated signaling and cytoskeletal signaling pathways by binding PIPKIγ in proximity of the cytoskeletal proteins talin and Cdc42. Our results support a model in which IQGAP1 mediates crosstalk between phosphoinositide signaling and the cytoskeleton to promote directed cell movement. IQGAP1 connects PI signaling to cytoskeletal reorganization

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Section: Discussionmentioning

confidence: 99%

Section: Iqgap1 Regulates β-Actin Complex Formation In Response To Prmentioning

confidence: 99%

IQGAP1 connects phosphoinositide signaling to cytoskeletal reorganization

Yerramilli

Ross

Lindberg³

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…The interaction of the MP part with talin results in the position and angle change of MP part, thus leading to the pistoning [102] and moving apart [187] of the transmembrane helices. A recent study showed that phosphatidylinositol 4,5-bisphosphate (PIP2) can interact with residue Arg995 within the TMD and break the salt-bridge when talin is bound, thus helping integrin activation [188]. …”

Section: Conformational Activationmentioning

confidence: 99%

“…This interaction is also thought to be necessary for integrin activation [204], because mutations of the membrane binding residues on F2 domain significantly decrease the binding of PAC-1 antibody, which is specific for activated α IIb β 3 integrin. A recent molecular dynamics study using atomistic molecular stimulation demonstrated that PIP2 and 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) are important for talin-mediated salt bridge breaking, which leads to spatial changes of the β TMD and leads to integrin activation [188]. …”

Section: Adaptor Proteins and Integrin Activationmentioning

confidence: 99%

Leukocyte arrest: Biomechanics and molecular mechanisms of β 2 integrin activation

Fan

Ley

2016

BIR

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Integrins are a group of heterodimeric transmembrane receptors that play essential roles in cell–cell and cell–matrix interaction. Integrins are important in many physiological processes and diseases. Integrins acquire affinity to their ligand by undergoing molecular conformational changes called activation. Here we review the molecular biomechanics during conformational changes of integrins, integrin functions in leukocyte biorheology (adhesive functions during rolling and arrest) and molecules involved in integrin activation.

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“…This “activated conformation” can be driven by binding of an extracellular ligand such as fibronectin, or by an “inside-out” mediated structural transition caused by intracellular phosphorylation events (46). As for other plasma membrane – F-actin interactions, there is evidence that PIP 2 participates in integrin-mediated coupling (47). …”

Section: Roles For Lipids In Actin Cytoskeleton Coupling To the Plmentioning

confidence: 99%

Roles for lipid heterogeneity in immunoreceptor signaling

Holowka

Baird

2016

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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Immune receptors that specifically recognize foreign antigens to activate leukocytes in adaptive immune responses belong to a family of multichain cell surface proteins. All of these contain immunoreceptor tyrosine-based activation motifs in one or more subunits that initiate signaling cascades following stimulated tyrosine phosphorylation by Src-family kinases. As highlighted in this review, lipids participate in this initial activation step, as well as in more downstream signaling steps. We summarize evidence for cholesterol-dependent ordered lipids serving to regulate the store-operated Ca2+ channel, Orai1, and we describe the sensitivity of Orai1 coupling to the ER Ca2+ sensor, STIM1, to inhibition by polyunsaturated fatty acids. Phosphoinositides play key roles in regulating STIM1-Orai1 coupling, as well as in the stimulated Ca2+ oscillations that are a consequence of IgE receptor signaling in mast cells. They also participate in the coupling between the plasma membrane and the actin cytoskeleton, which regulates immune receptor responses in T cells, B cells, and mast cells, both positively and negatively, depending on the cellular context. Recent studies show that other phospholipids with mostly saturated acylation also participate in coupling between receptors and the actin cytoskeleton. Lipid heterogeneity is a central feature of the intimate relationship between the plasma membrane and the actin cytoskeleton. The detailed nature of these interactions and how they are dynamically regulated to initiate and propagate receptor-mediated cell signaling are challenging questions for further investigation.

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PIP2 and Talin Join Forces to Activate Integrin

Cited by 27 publications

References 69 publications

IQGAP1 connects phosphoinositide signaling to cytoskeletal reorganization

IQGAP1 connects phosphoinositide signaling to cytoskeletal reorganization

Leukocyte arrest: Biomechanics and molecular mechanisms of β 2 integrin activation

Roles for lipid heterogeneity in immunoreceptor signaling

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