scholarly journals Allosteric feed-forward activation of AP-2 via FCHO-BMP2K axis promotes clathrin-mediated endocytosis

2019 ◽  
Author(s):  
Shikha T. Ramesh ◽  
Kolaparamba V. Navyasree ◽  
Anjitha B. Ashok ◽  
Nishada Qathoon ◽  
Suryasikha Mohanty ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Loss Of Function ◽  
Feed Forward ◽  
Temporal Regulation ◽  
Bona Fide ◽  
Gain And Loss ◽  
Spatio Temporal ◽  
Functional Inactivation ◽  
Zebrafish Embryogenesis

AbstractSpatio-temporal regulation of central adaptor complex, AP-2 is pivotal for clathrin-mediated endocytosis (CME). We recently discovered that FCHO proteins trigger clathrin-coated pit (CCP) formation by allosterically activating AP-2 on plasma membrane (Umasankar et al., 2014). Here, we demonstrate that this activation promotes AP-2 phosphorylation via recruitment and stabilization of BMP-2 inducible kinase (BMP2K), a bona fide AP-2 kinase leading to CCP maturation. Accordingly, BMP2K mislocalizes and degrades in FCHO knockout/ AP-2 depleted cells. Functional inactivation of kinase impairs AP-2 phosphorylation leading to altered lattice morphology and CME phenotypes reminiscent of CCP maturation defects. Reexpression of FCHO rescues AP-2 phosphorylation defects in FCHO knockout cells implying membrane activation of AP-2 is a prerequisite for kinase function. Furthermore, gain- and loss-of function phenotypes of FCHO and BMP2K are analogous and mirror altered AP-2 functions during zebrafish embryogenesis. Together, our findings reveal an in vivo allosteric feed-forward axis for operation of CME.

scholarly journals The scaffold-protein IQGAP1 enhances and spatially restricts the actin-nucleating activity of Diaphanous-related formin 1 (DIAPH1)

2020 ◽  
Vol 295 (10) ◽  
pp. 3134-3147 ◽  
Author(s):  
Anan Chen ◽  
Pam D. Arora ◽  
Christine C. Lai ◽  
John W. Copeland ◽  
Trevor F. Moraes ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Actin Filament ◽  
Intramolecular Interaction ◽  
Essential Feature ◽  
Temporal Regulation ◽  
Iq Motif ◽  
Sequential Binding ◽  
Spatio Temporal

The actin cytoskeleton is a dynamic array of filaments that undergoes rapid remodeling to drive many cellular processes. An essential feature of filament remodeling is the spatio-temporal regulation of actin filament nucleation. One family of actin filament nucleators, the Diaphanous-related formins, is activated by the binding of small G-proteins such as RhoA. However, RhoA only partially activates formins, suggesting that additional factors are required to fully activate the formin. Here we identify one such factor, IQ motif containing GTPase activating protein-1 (IQGAP1), which enhances RhoA-mediated activation of the Diaphanous-related formin (DIAPH1) and targets DIAPH1 to the plasma membrane. We find that the inhibitory intramolecular interaction within DIAPH1 is disrupted by the sequential binding of RhoA and IQGAP1. Binding of RhoA and IQGAP1 robustly stimulates DIAPH1-mediated actin filament nucleation in vitro. In contrast, the actin capping protein Flightless-I, in conjunction with RhoA, only weakly stimulates DIAPH1 activity. IQGAP1, but not Flightless-I, is required to recruit DIAPH1 to the plasma membrane where actin filaments are generated. These results indicate that IQGAP1 enhances RhoA-mediated activation of DIAPH1 in vivo. Collectively these data support a model where the combined action of RhoA and an enhancer ensures the spatio-temporal regulation of actin nucleation to stimulate robust and localized actin filament production in vivo.

scholarly journals Spatio-temporal regulation of calpain activity after experimental myocardial infarction in vivo

2021 ◽  
Vol 28 ◽  
pp. 101162
Author(s):  
Kun Zhang ◽  
Melissa M. Cremers ◽  
Stephan Wiedemann ◽  
David M. Poitz ◽  
Christian Pfluecke ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Experimental Myocardial Infarction ◽  
Calpain Activity ◽  
Temporal Regulation ◽  
Spatio Temporal

scholarly journals Apical polarity proteins recruit the RhoGEF Cysts to promote junctional myosin assembly

2019 ◽  
Vol 218 (10) ◽  
pp. 3397-3414 ◽  
Author(s):  
Jordan T. Silver ◽  
Frederik Wirtz-Peitz ◽  
Sérgio Simões ◽  
Milena Pellikka ◽  
Dong Yan ◽  
...  
Keyword(s):  
Rho Gtpases ◽  
Rho Gtpase ◽  
Adherens Junctions ◽  
Nucleotide Exchange ◽  
Temporal Regulation ◽  
Apical Polarity ◽  
Polarity Proteins ◽  
Spatio Temporal ◽  
Crumbs Complex

The spatio-temporal regulation of small Rho GTPases is crucial for the dynamic stability of epithelial tissues. However, how RhoGTPase activity is controlled during development remains largely unknown. To explore the regulation of Rho GTPases in vivo, we analyzed the Rho GTPase guanine nucleotide exchange factor (RhoGEF) Cysts, the Drosophila orthologue of mammalian p114RhoGEF, GEF-H1, p190RhoGEF, and AKAP-13. Loss of Cysts causes a phenotype that closely resembles the mutant phenotype of the apical polarity regulator Crumbs. This phenotype can be suppressed by the loss of basolateral polarity proteins, suggesting that Cysts is an integral component of the apical polarity protein network. We demonstrate that Cysts is recruited to the apico-lateral membrane through interactions with the Crumbs complex and Bazooka/Par3. Cysts activates Rho1 at adherens junctions and stabilizes junctional myosin. Junctional myosin depletion is similar in Cysts- and Crumbs-compromised embryos. Together, our findings indicate that Cysts is a downstream effector of the Crumbs complex and links apical polarity proteins to Rho1 and myosin activation at adherens junctions, supporting junctional integrity and epithelial polarity.

scholarly journals Gain and loss of function of ALS-related mutations of TARDBP (TDP-43) cause motor deficits in vivo

2010 ◽  
Vol 19 (15) ◽  
pp. 3102-3102 ◽  
Author(s):  
E. Kabashi ◽  
L. Lin ◽  
M. L. Tradewell ◽  
P. A. Dion ◽  
V. Bercier ◽  
...  
Keyword(s):  
Motor Deficits ◽  
Loss Of Function ◽  
Gain And Loss

Role of ESCRT component HD-PTP/PTPN23 in cancer

2017 ◽  
Vol 45 (3) ◽  
pp. 845-854 ◽  
Author(s):  
Marie-Claude Gingras ◽  
Jalal M. Kazan ◽  
Arnim Pause
Keyword(s):  
Plasma Membrane ◽  
Cancer Susceptibility ◽  
Tumour Suppressor ◽  
Tumour Suppressor Genes ◽  
Surface Receptors ◽  
Endosomal Sorting ◽  
Bona Fide

Sustained cellular signalling originated from the receptors located at the plasma membrane is widely associated with cancer susceptibility. Endosomal sorting and degradation of the cell surface receptors is therefore crucial to preventing chronic downstream signalling and tumorigenesis. Since the Endosomal Sorting Complexes Required for Transport (ESCRT) controls these processes, ESCRT components were proposed to act as tumour suppressor genes. However, the bona fide role of ESCRT components in tumorigenesis has not been clearly demonstrated. The ESCRT member HD-PTP/PTPN23 was recently identified as a novel haplo-insufficient tumour suppressor in vitro and in vivo, in mice and humans. In this mini-review, we outline the role of the ESCRT components in cancer and summarize the functions of HD-PTP/PTPN23 in tumorigenesis.

scholarly journals A Na,K-ATPase–Fodrin–Actin Membrane Cytoskeleton Complex is Required for Endothelial Fenestra Biogenesis

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1387
Author(s):  
Meihua Ju ◽  
Sofia Ioannidou ◽  
Peter Munro ◽  
Olli Rämö ◽  
Helena Vihinen ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Protein Composition ◽  
Loss Of Function ◽  
Membrane Pores ◽  
Membrane Cytoskeleton ◽  
Vascular Endothelia ◽  
Biochemical Analyses ◽  
Pore Protein

Fenestrae are transcellular plasma membrane pores that mediate blood–tissue exchange in specialised vascular endothelia. The composition and biogenesis of the fenestra remain enigmatic. We isolated and characterised the protein composition of large patches of fenestrated plasma membrane, termed sieve plates. Loss-of-function experiments demonstrated that two components of the sieve plate, moesin and annexin II, were positive and negative regulators of fenestra formation, respectively. Biochemical analyses showed that moesin is involved in the formation of an actin–fodrin submembrane cytoskeleton that was essential for fenestra formation. The link between the fodrin cytoskeleton and the plasma membrane involved the fenestral pore protein PV-1 and Na,K-ATPase, which is a key regulator of signalling during fenestra formation both in vitro and in vivo. These findings provide a conceptual framework for fenestra biogenesis, linking the dynamic changes in plasma membrane remodelling to the formation of a submembrane cytoskeletal signalling complex.

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