PI(4,5)P2-binding effector proteins for vesicle exocytosis

Martin, Thomas F.J.

doi:10.1016/j.bbalip.2014.09.017

Cited by 116 publications

(124 citation statements)

References 164 publications

(261 reference statements)

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“…A specialized Ca++-regulated exocytosis pathway provides a dramatic exception to this rule, and is by far the best characterized example of PIP2 clustering in cells (reviewed by (Martin, 2015)). Membrane fusion in all eukaryotic cells is mediated by SNARE proteins, integral membrane proteins present in the membranes of both prospective fusion partners (Jahn and Scheller, 2006).…”

Section: Pip2 and Protein Clustering In Cells: Syntaxin And Ca++-regumentioning

confidence: 98%

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PIP2Clustering: From model membranes to cells

Brown

2015

Chemistry and Physics of Lipids

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Section: Pip2 and Protein Clustering In Cells: Syntaxin And Ca++-regumentioning

confidence: 98%

“…Finally, I will consider a potential broader role for PIP2 downstream of membrane protein clustering. A number of excellent, more-detailed reviews of phosphoinositides have appeared recently (McLaughlin and Murray, 2005;Carlton and Cullen, 2005;Hilgemann, 2007;Saarikangas et al, 2010;Balla, 2013;Slochower et al, 2014;Martin, 2015).…”

Section: Introductionmentioning

confidence: 99%

PIP2Clustering: From model membranes to cells

Brown

2015

Chemistry and Physics of Lipids

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“…The fact that the control peptides (a different Arg 9 peptide and Kal-c KKED -Arg 9 ) were without effect minimizes concerns about the nonspecific effects of Kal-c-Arg 9 , as does its selective effect on regulated, but not basal, secretion (52). Understanding what the Kal-c peptide can do when not tethered to the CRAL_TRIO domain will inform future studies.…”

Section: Discussionmentioning

confidence: 99%

An N-terminal Amphipathic Helix Binds Phosphoinositides and Enhances Kalirin Sec14 Domain-mediated Membrane Interactions

Miller

Vishwanatha

Mains

et al. 2015

Journal of Biological Chemistry

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Background: Promoter usage determines the peptide preceding the lipid-binding KalSec14 domain.Results: Kalirin C-promoter encodes an amphipathic helix, which interacts with phosphoinositides, localizes to the trans-Golgi network, alters KalSec14 interactions with cell membranes, and stimulates secretion. Conclusion: Sec14 domain function is altered by the preceding phosphoinositide-binding amphipathic helix. Significance: Kalirin function is expected to vary with promoter choice.Previous studies revealed an essential role for the lipid-binding Sec14 domain of kalirin (KalSec14), but its mechanism of action is not well understood. Because alternative promoter usage appends unique N-terminal peptides to the KalSec14 domain, we used biophysical, biochemical, and cell biological approaches to examine the two major products, bKalSec14 and cKalSec14. Promoter B encodes a charged, unstructured peptide, whereas promoter C encodes an amphipathic helix (Kal-Chelix). Both bKalSec14 and cKalSec14 interacted with lipids in PIP strip and liposome flotation assays, with significantly greater binding by cKalSec14 in both assays. Disruption of the hydrophobic face of the Kal-C-helix in cKalSec14 KKED eliminated its increased liposome binding. Although cKalSec14 showed significantly reduced binding to liposomes lacking phosphatidylinositol phosphates or cholesterol, liposome binding by bKalSec14 and cKalSec14 KKED was not affected. When expressed in AtT-20 cells, bKalSec14-GFP was diffusely localized, whereas cKalSec14-GFP localized to the trans-Golgi network and secretory granules. The amphipathic C-helix was sufficient for this localization. When AtT-20 cells were treated with a cell-permeant derivative of the Kal-C-helix (Kal-C-helixArg 9 ), we observed increased secretion of a product stored in mature secretory granules, with no effect on basal secretion; a cell-permeant control peptide (Kal-C-helix KKED -Arg 9 ) did not have this effect. Through its ability to control expression of a novel, phosphoinositide-binding amphipathic helix, Kalrn promoter usage is expected to affect function.Kalirin is a Rho family GDP/GTP exchange factor (GEF) 2 with widespread cell signaling functions. Alternative splicing of the Kalrn gene gives rise to multiple isoforms that are developmentally regulated and tissue-specific. Kalirin7 (Kal7), found exclusively in the nervous system, is the major isoform in the adult brain and is essential for synaptic structure and function (1-6). Kal9 and Kal12 are expressed throughout development, both within and outside of the nervous system. Kal9/12 are crucial for normal neurite outgrowth, endocrine and bone homeostasis, and smooth muscle cell migration (7-10). Kalirin proteins have multiple functional domains, with major splice variants differing at their C termini. Kal7, -9, and -12 share identical N-terminal Sec14 domains, which are followed by nine spectrin repeats and tandem Dbl and pleckstrin homology domains (GEF1), activating Rac1 and RhoG (Fig. 1A). Only Kal7 terminates in a PDZ binding motif. Kal9...

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“…3I). In vivo, a high concentration of phosphatidylserine at the PM may compensate for the low affinity of phosphatidylserine for the Rho1 poly-basic sequence, as phosphatidylserine accounts for more than 10% of PM phospholipids, whereas PI(4,5)P 2 composes only 1% (Fairn and Grinstein, 2012;Leventis and Grinstein, 2010;van Meer et al, 2008;Martin, 2015). Nanoclustering of phosphatidylserine at the PM might also contribute to Rho1 binding, as is the case for human K-Ras (Zhou et al, 2015).…”

Section: Ypk1/ypk2 Support Rho1 Localization To the Bud Cortex Duringmentioning

confidence: 99%

Ypk1 and Ypk2 kinases maintain Rho1 at the plasma membrane by flippase-dependent lipid remodeling after membrane stresses

Hatakeyama

Kono

Yoshida

2017

Journal of Cell Science

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The plasma membrane (PM) is frequently challenged by mechanical stresses. In budding yeast, TORC2-Ypk1/Ypk2 kinase cascade plays a crucial role in PM stress responses by reorganizing the actin cytoskeleton via Rho1 GTPase. However, the molecular mechanism by which TORC2-Ypk1/Ypk2 regulates Rho1 is not well defined. Here, we found that Ypk1/Ypk2 maintain PM localization of Rho1 under PM stress via spatial reorganization of the lipids including phosphatidylserine. Genetic evidence suggests that this process is mediated by the Lem3-containing lipid flippase. We propose that lipid remodeling mediated by the TORC2-Ypk1/Ypk2-Lem3 axis is a backup mechanism for PM anchoring of Rho1 after PM stressinduced acute degradation of phosphatidylinositol 4,5-bisphosphate [PI(4,5)P 2 ], which is responsible for Rho1 localization under normal conditions. Since all the signaling molecules studied here are conserved in higher eukaryotes, our findings might represent a general mechanism to cope with PM stress.

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PI(4,5)P2-binding effector proteins for vesicle exocytosis

Cited by 116 publications

References 164 publications

PIP2Clustering: From model membranes to cells

PIP2Clustering: From model membranes to cells

An N-terminal Amphipathic Helix Binds Phosphoinositides and Enhances Kalirin Sec14 Domain-mediated Membrane Interactions

Ypk1 and Ypk2 kinases maintain Rho1 at the plasma membrane by flippase-dependent lipid remodeling after membrane stresses

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