Faciogenital Dysplasia Protein (FGD1) Regulates Export of Cargo Proteins from the Golgi Complex via Cdc42 Activation

Egorov, Mikhail V.; Capestrano, Mariagrazia; Vorontsova, Olesya A.; Pentima, Alessio Di; Egorova, Anastasia V.; Mariggiò, Stefania; Ayala, Inmaculada; Tetè, Stefano; Gorski, Jerome L.; Luini, Alberto; Buccione, Roberto; Polishchuk, Roman

doi:10.1091/mbc.e08-11-1136

Cited by 51 publications

(63 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our results provide the basis of a molecular mechanism involving Fgd1 and cortactin at the onset of podosome assembly. It is worth pointing out that Fgd1 has been shown is important for export from the Golgi bodies in some cells (9). Therefore, we cannot exclude that Fgd1 depletion also affects protein export from the Golgi bodies to the cell surface.…”

Section: Discussionmentioning

confidence: 89%

See 1 more Smart Citation

The Aarskog-Scott Syndrome Protein Fgd1 Regulates Podosome Formation and Extracellular Matrix Remodeling in Transforming Growth Factor β-Stimulated Aortic Endothelial Cells

Daubon

Buccione

Génot

2011

Molecular and Cellular Biology

Self Cite

View full text Add to dashboard Cite

Podosomes are dynamic actin-rich adhesion plasma membrane microdomains endowed with extracellular matrix-degrading activities. In aortic endothelial cells, podosomes are induced by transforming growth factor ␤ (TGF-␤), but how this occurs is largely unknown. It is thought that, in endothelial cells, podosomes play a role in vessel remodeling and/or in breaching anatomical barriers. We demonstrate here that, in bovine aortic endothelial cells, that the Cdc42-specific guanine exchange factor (GEF) Fgd1 is expressed and regulated by TGF-␤ to induce Cdc42-dependent podosome assembly. Within 15 min of TGF-␤ stimulation, Fgd1, but none of the other tested Cdc42 GEFs, undergoes tyrosine phosphorylation, associates with Cdc42, and translocates to the subcortical cytoskeleton via a cortactin-dependent mechanism. Small interfering RNA-mediated Fgd1 knockdown inhibits TGF-␤-induced Cdc42 activation. Fgd1 depletion also reduces podosome formation and associated matrix degradation and these defects are rescued by reexpression of Fgd1. Although overexpression of Fgd1 does not promote podosome formation per se, it enhances TGF-␤-induced matrix degradation. Our results identify Fgd1 as a TGF-␤-regulated GEF and, as such, the first GEF to be involved in the process of cytokine-induced podosome formation. Our findings reveal the involvement of Fgd1 in endothelial cell biology and open up new avenues to study its role in vascular pathophysiology.The cytokine transforming growth factor ␤ (TGF-␤) induces pleiotropic effects. It is a pivotal regulator of vascular homeostasis, in particular in the arterial tree, during adult life (15), but how it fulfils this particular role remains unclear. We recently uncovered a novel role for TGF-␤ in endothelial cell physiology. In the cultured bovine aortic endothelial (BAE) cell model, TGF-␤ was found to remodel the actin cytoskeleton giving rise to the formation of podosomes. These typically occur in large, ring-shaped clusters of about 8 m in diameter (podosome superstructures also termed rosettes) (32). Podosomes are specialized plasma membrane actin-based microdo-

show abstract

Section: Discussionmentioning

confidence: 89%

“…The myc-Fgd1-RKB3 fusion construct contains deletions of residues 1 to 391 and 790 at the C terminus (25,38). The GFP-Fgd1-2DBDEL fusion construct contains deletions of residues 146 to 188 and 730 at the C terminus (3,9). All Fgd1 encoding plasmids were obtained from J. L. Gorski (University of Michigan) (3).…”

Section: Methodsmentioning

confidence: 99%

The Aarskog-Scott Syndrome Protein Fgd1 Regulates Podosome Formation and Extracellular Matrix Remodeling in Transforming Growth Factor β-Stimulated Aortic Endothelial Cells

Daubon

Buccione

Génot

2011

Molecular and Cellular Biology

Self Cite

View full text Add to dashboard Cite

show abstract

“…FGD1 encodes a guanine nucleotide exchange factor (GEF) that specifically activates the Cdc42 (Whitehead et al 1998;Egorov et al 2009). Cdc42 is predicted to play important roles in skeletal development.…”

Section: Discussionmentioning

confidence: 99%

Signaling Cascades Governing Cdc42-Mediated Chondrogenic Differentiation and Mensenchymal Condensation

Wang

et al. 2016

Genetics

View full text Add to dashboard Cite

Endochondral ossification consists of successive steps of chondrocyte differentiation, including mesenchymal condensation, differentiation of chondrocytes, and hypertrophy followed by mineralization and ossification. Loss-of-function studies have revealed that abnormal growth plate cartilage of the Cdc42 mutant contributes to the defects in endochondral bone formation. Here, we have investigated the roles of Cdc42 in osteogenesis and signaling cascades governing Cdc42-mediated chondrogenic differentiation. Though deletion of Cdc42 in limb mesenchymal progenitors led to severe defects in endochondral ossification, either ablation of Cdc42 in limb preosteoblasts or knockdown of Cdc42 in vitro had no obvious effects on bone formation and osteoblast differentiation. However, in Cdc42 mutant limb buds, loss of Cdc42 in mesenchymal progenitors led to marked inactivation of p38 and Smad1/5, and in micromass cultures, Cdc42 lay on the upstream of p38 to activate Smad1/5 in bone morphogenetic protein-2-induced mesenchymal condensation. Finally, Cdc42 also lay on the upstream of protein kinase B to transactivate Sox9 and subsequently induced the expression of chondrocyte differential marker in transforming growth factor-b1-induced chondrogenesis. Taken together, by using biochemical and genetic approaches, we have demonstrated that Cdc42 is involved not in osteogenesis but in chondrogenesis in which the BMP2/Cdc42/Pak/p38/Smad signaling module promotes mesenchymal condensation and the TGF-b/Cdc42/Pak/Akt/Sox9 signaling module facilitates chondrogenic differentiation. KEYWORDS Cdc42; condensation; osteoblast; chondrocyte S EVERAL successive steps, including mesenchymal condensation of undifferentiated cells, chondrocyte differentiation, proliferation of chondrocytes, and differentiation into hypertrophic chondrocytes followed by mineralization and ossification, exist in the process of endochondral ossification (Long and Ornitz 2013). Mesenchymal condensation is a prerequisite for chondrogenesis and is facilitated by cell adhesion molecules. Upregulation of cell adhesion proteins such as N-cadherin is a hallmark of condensing cells, whereas loss of cell adhesion molecules is able to abolish condensation (Delise and Tuan 2002;Bobick et al. 2009). The molecular mechanisms governing condensation are not fully understood, though several genes have been implicated in this process such as bone morphogenic proteins (BMPs) and SRY (sex determining region Y)-box 9 (Sox9) (Fromental-Ramain et al. 1996;Wada et al. 1998;Lu et al. 2008). Conditional inactivationof Sox9 in limb mesenchymal progenitors leads to the absence of condensations, while simultaneous deletion of Bmp2 and Bmp4 in limb mesenchymes leads to the loss of zeugopod elements and to defective joint articulations (Reversade et al. 2005). During endochondral ossification, condensed cells undergo the differentiation into chondrocytes that secrete an abundance of cartilage matrices including types II, IX, and XI collagen. Sox9 is also the earliest known transcription...

show abstract

“…In addition, expression of the DH and PH domains or the DH domain alone induces G1 cell cycle progression and entry into S phase as efficiently as constitutively active CDC42, suggesting that FGD1 facilitates G1 progression both through CDC42-dependent and CDC42-independent mechanisms (Nagata et al, 1998). Finally, recent data suggest that through the modulation of CDC42 activation, FGD1 is involved in the regulation of secretory protein export from the Golgi complex, the central processing unit of the secretory pathway (Egorov et al, 2009). Together, the data converge in positioning FGD1 upstream of CDC42 in these events (Fig.…”

Section: Fgd1 In Ecm Remodelling 3267mentioning

confidence: 99%

“…FGD1 also regulates ECM remodelling through the formation of invadopodia in tumour cells or podosomes in endothelial cells (Daubon et al, 2011). Finally, FGD1 controls the export of cargo proteins from the Golgi complex through CDC42 activation (Egorov et al, 2009). The FGD1 SH3-binding domain binds directly to the SH3 domain of mAbp1 or cortactin (Hou et al, 2003), and FGD1-cortactin binding promotes CDC42-independent actin assembly by the Arp2/3 complex (Kim et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

FGD1 as a central regulator of extracellular matrix remodelling – lessons from faciogenital dysplasia

Génot

Daubon

Sorrentino

et al. 2012

Journal of Cell Science

Self Cite

View full text Add to dashboard Cite

SummaryDisabling mutations in the FGD1 gene cause faciogenital dysplasia (also known as Aarskog-Scott syndrome), a human X-linked developmental disorder that results in disproportionately short stature, facial, skeletal and urogenital anomalies, and in a number of cases, mild mental retardation. FGD1 encodes the guanine nucleotide exchange factor FGD1, which is specific for the Rho GTPase cell division cycle 42 (CDC42). CDC42 controls cytoskeleton-dependent membrane rearrangements, transcriptional activation, secretory membrane trafficking, G1 transition during the cell cycle and tumorigenic transformation. The cellular mechanisms by which FGD1 mutations lead to the hallmark skeletal deformations of faciogenital dysplasia remain unclear, but the pathology of the disease, as well as some recent discoveries, clearly show that the protein is involved in the regulation of bone development. Two recent studies unveiled new potential functions of FGD1, in particular, its involvement in the regulation of the formation and function of invadopodia and podosomes, which are cellular structures devoted to degradation of the extracellular matrix in tumour and endothelial cells. Here, we discuss the hypothesis that FGD1 might be an important regulator of events controlling extracellular matrix remodelling and possibly cell invasion in physiological and pathological settings. Additionally, we focus on how studying the cell biology of FGD1 might help us to connect the dots that link CDC42 signalling with remodelling of the extracellular matrix (ECM) in physiology and complex diseases, while, at the same time, furthering our understanding of the pathogenesis of faciogenital dysplasia.

show abstract

Faciogenital Dysplasia Protein (FGD1) Regulates Export of Cargo Proteins from the Golgi Complex via Cdc42 Activation

Cited by 51 publications

References 35 publications

The Aarskog-Scott Syndrome Protein Fgd1 Regulates Podosome Formation and Extracellular Matrix Remodeling in Transforming Growth Factor β-Stimulated Aortic Endothelial Cells

The Aarskog-Scott Syndrome Protein Fgd1 Regulates Podosome Formation and Extracellular Matrix Remodeling in Transforming Growth Factor β-Stimulated Aortic Endothelial Cells

Signaling Cascades Governing Cdc42-Mediated Chondrogenic Differentiation and Mensenchymal Condensation

FGD1 as a central regulator of extracellular matrix remodelling – lessons from faciogenital dysplasia

Contact Info

Product

Resources

About