Significance of the Tks4 scaffold protein in bone tissue homeostasis

Vas, Virag; Körmendi, Szandra; Brody, Andrea; Kudlik, Gyöngyi; Szeder, Bálint; Mező, Diána; Kállai, Dóra; Koprivanacz, Kitti; Merő, Balázs; Dülk, Metta; Tóvári, József; Vajdovich, Péter; Senel, Sukriye Neslihan; Özcan, İlknur; Helyes, Zsuzsanna; Dobó‐Nagy, Csaba; Buday, László

doi:10.1038/s41598-019-42250-6

Cited by 13 publications

(17 citation statements)

References 33 publications

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“…Recently, some data have suggested a positive correlation between BAT function and bone mass [63,64,65,66], indicating that a direct or indirect relationship exists between bone remodeling and brown adipocyte biology. Therefore, it is important to point out that the reduced iBAT size in the Tks4-KO mice [14] was accompanied by an osteoporotic-like bone phenotype [18]. Furthermore, Tks4 has already been identified as a regulator of osteogenic differentiation in BM-MSCs [14]: therefore, the relationship between bone porosity and the altered BAT phenotype identified in this model system is intriguing, and it supports the notion of an interdependence between brown adipocyte function and bone homeostasis.…”

Section: Discussionmentioning

confidence: 99%

“…Mice were maintained and handled in accordance with the Guidelines for Accommodation and Care of Animals (European Convention for the Protection of Vertebrate Animals Used for Experimental and Other Scientific Purposes). The Tks4-KO mice (in the C57Bl/6 genetic background) were originally developed by TaconicArtemis GmbH (Cologne, Germany) [14,18]. The fifth and sixth coding exons of the Sh3pxd2b gene were flanked by loxP sites, and the floxed exons were then excised via Cre-mediated recombination in the germ line, resulting in inactivation of the Sh3pxd2b gene.…”

Section: Methodsmentioning

confidence: 99%

“…This disease is characterized by bone abnormalities, such as kyphosis and craniofacial deformities, cardiac disease due to valve or septal defects, glaucoma, and in some cases low adipose tissue depot weight [15,16,17]. Loss of Tks4 has recently also been shown to disturb bone formation, ultimately leading to osteoporosis [18].…”

Section: Introductionmentioning

confidence: 99%

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Analysis of Tks4 Knockout Mice Suggests a Role for Tks4 in Adipose Tissue Homeostasis in the Context of Beigeing

Vas

Háhner

Kudlik

et al. 2019

Cells

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Obesity and adipocyte malfunction are related to and arise as consequences of disturbances in signaling pathways. Tyrosine kinase substrate with four Src homology 3 domains (Tks4) is a scaffold protein that establishes a platform for signaling cascade molecules during podosome formation and epidermal growth factor receptor (EGFR) signaling. Several lines of evidence have also suggested that Tks4 has a role in adipocyte biology; however, its roles in the various types of adipocytes at the cellular level and in transcriptional regulation have not been studied. Therefore, we hypothesized that Tks4 functions as an organizing molecule in signaling networks that regulate adipocyte homeostasis. Our aims were to study the white and brown adipose depots of Tks4 knockout (KO) mice using immunohistology and western blotting and to analyze gene expression changes regulated by the white, brown, and beige adipocyte-related transcription factors via a PCR array. Based on morphological differences in the Tks4-KO adipocytes and increased uncoupling protein 1 (UCP1) expression in the white adipose tissue (WAT) of Tks4-KO mice, we concluded that the beigeing process was more robust in the WAT of Tks4-KO mice compared to the wild-type animals. Furthermore, in the Tks4-KO WAT, the expression profile of peroxisome proliferator-activated receptor gamma (PPARγ)-regulated adipogenesis-related genes was shifted in favor of the appearance of beige-like cells. These results suggest that Tks4 and its downstream signaling partners are novel regulators of adipocyte functions and PPARγ-directed white to beige adipose tissue conversion.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Analysis of Tks4 Knockout Mice Suggests a Role for Tks4 in Adipose Tissue Homeostasis in the Context of Beigeing

Vas

Háhner

Kudlik

et al. 2019

Cells

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“…The protein product of the SH3PXD2B gene, Tks4, belongs to the family of scaffold proteins [23]. Tks4 is involved in podosome formation, cell migration, mesenchymal stem cell differentiation, adipose tissue beigeing, and bone trabecular formation [23,24,25,26,27,28,29]. Inactivating mutations in the SH3PXD2B gene cause a rare genetic disorder known as Frank-ter-Haar syndrome (FTHS, OMIM:249420) [30].…”

Section: Introductionmentioning

confidence: 99%

Absence of the Tks4 Scaffold Protein Induces Epithelial-Mesenchymal Transition-Like Changes in Human Colon Cancer Cells

Szeder

Tarnoki-Zach

Lakatos

et al. 2019

Cells

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Epithelial to mesenchymal transition (EMT) is a multipurpose process involved in wound healing, development, and certain pathological processes, such as metastasis formation. The Tks4 scaffold protein has been implicated in cancer progression; however, its role in oncogenesis is not well defined. In this study, the function of Tks4 was investigated in HCT116 colon cancer cells by knocking the protein out using the CRISPR/Cas9 system. Surprisingly, the absence of Tks4 induced significant changes in cell morphology, motility, adhesion and expression, and localization of E-cadherin, which are all considered as hallmarks of EMT. In agreement with these findings, the marked appearance of fibronectin, a marker of the mesenchymal phenotype, was also observed in Tks4-KO cells. Analysis of the expression of well-known EMT transcription factors revealed that Snail2 was strongly overexpressed in cells lacking Tks4. Tks4-KO cells showed increased motility and decreased cell–cell attachment. Collagen matrix invasion assays demonstrated the abundance of invasive solitary cells. Finally, the reintroduction of Tks4 protein in the Tks4-KO cells restored the expression levels of relevant key transcription factors, suggesting that the Tks4 scaffold protein has a specific and novel role in EMT regulation and cancer progression.

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“…Mutations in the Tks4 gene lead to a rare genetic disease called Frank-ter Haar Syndrome (FTHS) [ 22 ]. In FTHS-affected individuals, the development of several tissues is disturbed [ 23 , 24 ], showing that Tks4 has an effect on bone, fat, and mesenchymal stem cells [ 25 , 26 ]. Moreover, Tks4 has an instructive role in an epithelial mesenchymal (EMT)-like transition in cancer cells [ 27 ].…”

Section: Introductionmentioning

confidence: 99%

Characterization of the Intramolecular Interactions and Regulatory Mechanisms of the Scaffold Protein Tks4

Merő

Koprivanacz

Cserkaszky

et al. 2021

IJMS

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The scaffold protein Tks4 is a member of the p47phox-related organizer superfamily. It plays a key role in cell motility by being essential for the formation of podosomes and invadopodia. In addition, Tks4 is involved in the epidermal growth factor (EGF) signaling pathway, in which EGF induces the translocation of Tks4 from the cytoplasm to the plasma membrane. The evolutionarily-related protein p47phox and Tks4 share many similarities in their N-terminal region: a phosphoinositide-binding PX domain is followed by two SH3 domains (so called “tandem SH3”) and a proline-rich region (PRR). In p47phox, the PRR is followed by a relatively short, disordered C-terminal tail region containing multiple phosphorylation sites. These play a key role in the regulation of the protein. In Tks4, the PRR is followed by a third and a fourth SH3 domain connected by a long (~420 residues) unstructured region. In p47phox, the tandem SH3 domain binds the PRR while the first SH3 domain interacts with the PX domain, thereby preventing its binding to the membrane. Based on the conserved structural features of p47phox and Tks4 and the fact that an intramolecular interaction between the third SH3 and the PX domains of Tks4 has already been reported, we hypothesized that Tks4 is similarly regulated by autoinhibition. In this study, we showed, via fluorescence-based titrations, MST, ITC, and SAXS measurements, that the tandem SH3 domain of Tks4 binds the PRR and that the PX domain interacts with the third SH3 domain. We also investigated a phosphomimicking Thr-to-Glu point mutation in the PRR as a possible regulator of intramolecular interactions. Phosphatidylinositol-3-phosphate (PtdIns(3)P) was identified as the main binding partner of the PX domain via lipid-binding assays. In truncated Tks4 fragments, the presence of the tandem SH3, together with the PRR, reduced PtdIns(3)P binding, while the presence of the third SH3 domain led to complete inhibition.

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Significance of the Tks4 scaffold protein in bone tissue homeostasis

Cited by 13 publications

References 33 publications

Analysis of Tks4 Knockout Mice Suggests a Role for Tks4 in Adipose Tissue Homeostasis in the Context of Beigeing

Analysis of Tks4 Knockout Mice Suggests a Role for Tks4 in Adipose Tissue Homeostasis in the Context of Beigeing

Absence of the Tks4 Scaffold Protein Induces Epithelial-Mesenchymal Transition-Like Changes in Human Colon Cancer Cells

Characterization of the Intramolecular Interactions and Regulatory Mechanisms of the Scaffold Protein Tks4

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