Phosphorylation-mediated 14-3-3 Protein Binding Regulates the Function of the Rho-specific Guanine Nucleotide Exchange Factor (RhoGEF) Syx*

Ngok, Siu P.; Geyer, Rory; Kourtidis, Antonis; Störz, Peter; Anastasiadis, Panos Z.

doi:10.1074/jbc.m112.432682

Cited by 17 publications

(19 citation statements)

References 29 publications

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“…Recently, two reports have shown that Syx is phosphorylated by protein kinase D1 (PKD1) on Ser-92, Ser-806, and Ser-938. 6,76 Through mutational analysis, it was found that phosphorylation of Ser-92 and Ser-938 results in binding of Syx to 14-3-3 proteins. The authors speculate that phosphorylation of Ser-806 may induce conformational changes of Syx that may allow for dimerization of the 14-3-3 proteins bound to the N-and C-termini of Syx.…”

Section: Regulation Of Gefs By Ser/thr Kinasesmentioning

confidence: 99%

Phosphorylation-mediated regulation of GEFs for RhoA

Patel

Karginov

2013

Cell Adhesion & Migration

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Section: Regulation Of Gefs By Ser/thr Kinasesmentioning

confidence: 99%

Phosphorylation-mediated regulation of GEFs for RhoA

Patel

Karginov

2013

Cell Adhesion & Migration

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“…The level of activated RhoA was determined in cells using rhotekin pull-down assays as previously described (Ngok et al, 2013). Briefly, cells (HUVECs, MDCK and HeLa) were grown to confluence in 6 cm plates and lysed with Rho activity lysis buffer (20 mM HEPES, 100 mM NaCl, 10% glycerol, 0.5% NP40, 0.2% deoxycholic acid, 100 mM MgCl 2 , pH 7.5); cell lysates were collected and cleared by centrifugation, the supernatants were then incubated with reconstituted GST-fused rhotekin-RBD protein beads (Cytoskeleton) at 4˚C for 45 minutes, beads were washed three times with the lysis buffer and bound proteins were eluted by boiling in loading buffer.…”

Section: Rho Activity Assaymentioning

confidence: 99%

TEM4 is a junctional RhoGEF required for cell-cell adhesion, monolayer integrity, and barrier function

Ngok

Geyer

Kourtidis

et al. 2013

Journal of Cell Science

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SummarySignaling events mediated by Rho family GTPases orchestrate cytoskeletal dynamics and cell junction formation. The activation of Rho GTPases is tightly regulated by guanine-nucleotide-exchange factors (GEFs). In this study, we identified a novel Rho-specific GEF called TEM4 (tumor endothelial marker 4) that associates with multiple members of the cadherin-catenin complex and with several cytoskeleton-associated proteins. Depending on confluence, TEM4 localized to either actin stress fibers or areas of cell-cell contact. The junctional localization of TEM4 was independent of actin binding. Depletion of endogenous TEM4 by shRNAs impaired Madin-Darby canine kidney (MDCK) and human umbilical vein endothelial cell (HUVEC) cell junctions, disrupted MDCK acini formation in 3D culture and negatively affected endothelial barrier function. Taken together, our findings implicate TEM4 as a novel and crucial junctional Rho GEF that regulates cell junction integrity and epithelial and endothelial cell function.

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“…For a number of the prospective targets, phosphorylation is known to negatively regulate RhoA signaling, although GCKIII kinases have not been implicated in most cases. For example, serine phosphorylation of RhoA inhibits its activity in vivo (Ellerbroek et al, 2003), phosphorylation of Smurf1 by protein kinase A increases the degradation of RhoA (Cheng et al, 2011), phosphorylation of the junctional RhoGEF, Syx, reduces its junctional localization and ability to activate RhoA-mDia signaling (Ngok et al, 2013, Ngok et al, 2012), and both Mst3 and Mst4 are important for phosphorylation and activation of ERM proteins, at least in the case of Mst4 in a Ccm3-dependent manner (Fidalgo et al, 2012). Moreover, Mst3 was found to interact with the Rho family GEF, Vav2 in a two-hybrid interaction assay (Thalappilly et al, 2008).…”

Section: The Role Of Stripak In Diseasesmentioning

confidence: 99%

STRIPAK complexes: Structure, biological function, and involvement in human diseases

Hwang

Pallas

2014

The International Journal of Biochemistry & Cell Biology

213

273

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The mammalian striatin family consists of three proteins, striatin, S/G2 nuclear autoantigen, and zinedin. Striatin family members have no intrinsic catalytic activity, but rather function as scaffolding proteins. Remarkably, they organize multiple diverse, large signaling complexes that participate in a variety of cellular processes. Moreover, they appear to be regulatory/targeting subunits for the major eukaryotic serine/threonine protein phosphatase 2A. In addition, striatin family members associate with germinal center kinase III kinases as well as other novel components, earning these assemblies the name striatin-interacting phosphatase and kinase (STRIPAK) complexes. Recently, there has been a great increase in functional and mechanistic studies aimed at identifying and understanding the roles of STRIPAK–like complexes in cellular processes of multiple organisms. These studies have identified novel STRIPAK or STRIPAK-like complexes and have explored their roles in specific signaling pathways. Together, the results of these studies have sparked increased interest in striatin family complexes because they have revealed roles in signaling, cell cycle control, apoptosis, vesicular trafficking, Golgi assembly, cell polarity, cell migration, neural and vascular development, and cardiac function. Moreover, STRIPAK complexes have been connected to clinical conditions, including cardiac disease, diabetes, autism, and cerebral cavernous malformation. In this review, we discuss the expression, localization, and protein domain structure of striatin family members. Then we consider the diverse complexes these proteins and their homologs form in various organisms, emphasizing what is known regarding function and regulation. Finally, we will explore possible roles of striatin family complexes in disease, especially cerebral cavernous malformation.

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Phosphorylation-mediated 14-3-3 Protein Binding Regulates the Function of the Rho-specific Guanine Nucleotide Exchange Factor (RhoGEF) Syx*

Cited by 17 publications

References 29 publications

Phosphorylation-mediated regulation of GEFs for RhoA

Phosphorylation-mediated regulation of GEFs for RhoA

TEM4 is a junctional RhoGEF required for cell-cell adhesion, monolayer integrity, and barrier function

STRIPAK complexes: Structure, biological function, and involvement in human diseases

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