Src Homology 2 Domain Containing Protein 5 (SH2D5) Binds the Breakpoint Cluster Region Protein, BCR, and Regulates Levels of Rac1-GTP

Gray, Elizabeth J.; Petsalaki, Evangelia; Bagshaw, Richard D.; Stacey, Melissa M.; Rocks, Oliver; Gingras, Anne‐Claude; Pawson, Tony

doi:10.1074/jbc.m114.615112

Cited by 17 publications

(17 citation statements)

References 30 publications

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“…Moreover, there was evidence showing that CXCL8‐induced endothelial cell migration required the activation of Rac1. Previous studies demonstrated that Src played pivotal roles in regulating Rac1 function (19, 20). We then tried to investigate whether there is a relationship between CXCR2‐Src and Rac1 during EPC migration.…”

Section: Resultsmentioning

confidence: 99%

“…The activation of Rac1 mediates the migration of various types of cells, including EPCs (39). Previous reports indicate that that Src plays a crucial role in regulating Rac1 (19, 20). Consistently, we found that, in vitro and in vivo , the Rac1 inhibitor had a similar suppressive influence to the Src inhibitor regarding EPC migration, vascularization, and bone repair.…”

Section: Discussionmentioning

confidence: 99%

“…There is evidence that cell migration induced by CXCL8 requires the nonreceptor tyrosine kinase focal adhesion kinase (FAK) and steroid receptor coactivator (Src) (17, 18). Src regulates a number of signaling pathways with respect to cell migration, and evidence suggests that it has a vital role in regulating the Rho GTPases, which are pivotal molecules involving lamellipodia formation (19, 20).…”

mentioning

confidence: 99%

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Mesenchymal stem cells promote endothelial progenitor cell migration, vascularization, and bone repair in tissue‐engineered constructs via activating CXCR2‐Src‐PKL/Vav2‐Rac1

Yang

Yin

et al. 2018

FASEB j.

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Tissue-engineered constructs (TECs) hold great promise for treating large bone defects. Incorporated mesenchymal stem cells (MSCs) can facilitate the vascularization of TECs. Nevertheless, the underlying mechanism remains ambiguous. Here we analyzed the roles of C-X-C chemokine receptor 2 (CXCR2) and its downstream signal pathways in MSC-induced endothelial progenitor cell (EPC) migration. Transwell assays and immunofluorescence staining were performed for cell migration analysis in vitro and in vivo, respectively. A series of signal inhibitors and short hairpin RNA was used for screening essential signaling molecules. We found that blockade of CXCR2 abolished the migration of EPCs toward MSCs as well as subsequent vascularization and bone repair in TECs. Moreover, screening results suggested that steroid receptor coactivator (Src) acted as a predominant downstream effector of CXCR2. Further molecular biologic and histomorphological experiments revealed that the action of Src required the phosphorylation of ras-related C3 botulinum toxin substrate 1 (Rac1), which was pivotal for the development of lamellipodia and filopodia. The phosphorylation and colocalization of paxillin kinase linker (PKL) and vav guanine nucleotide exchange factor 2 (Vav2) were essential for the activation of Rac1. Therefore, we demonstrated that MSCs promoted EPC migration via activating CXCR2 and its downstream Src-PKL/Vav2-Rac1 signaling pathway. These findings unveiled the molecular mechanism in the vascularization of TECs and were expected to provide novel targets for efficacy improvement.-Li, Z., Yang, A., Yin, X., Dong, S., Luo, F., Dou, C., Lan, X., Xie, Z., Hou, T., Xu, J., Xing, J. Mesenchymal stem cells promote endothelial progenitor cell migration, vascularization, and bone repair in tissue-engineered constructs via activating CXCR2-Src-PKL/Vav2-Rac1.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Mesenchymal stem cells promote endothelial progenitor cell migration, vascularization, and bone repair in tissue‐engineered constructs via activating CXCR2‐Src‐PKL/Vav2‐Rac1

Yang

Yin

et al. 2018

FASEB j.

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“…It has been suggested to play a role in cell proliferation, and functions as an activator of the ERK1/2 and p38MAPK signaling pathways [29]. Finally, the third highly significant CpG (cg03472655) was located in the gene SH2D5 (SH2 Domain Containing 5 protein) which is an adaptor-like protein expressed mainly in the brain [30]. Cg03472655 is situated in a CpG island in the first exon of the genea region that appears to be actively regulated.…”

Section: Discussionmentioning

confidence: 99%

Hormone therapy use and breast tissue DNA methylation: analysis of epigenome wide data from the normal breast study

Harlid

Kirk

et al. 2019

Epigenetics

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Hormone therapy (HT) is associated with increased risk of breast cancer, strongly dependent on type, duration, and recency of use. HT use could affect cancer risk by changing breast tissue transcriptional programs. We hypothesize that these changes are preceded by changes in DNA methylation. To explore this hypothesis we used histologically normal-appearing breast tissue from the Normal Breast Study (NBS). DNA methylation β-values were obtained using the Illumina HumanMethylation 450 BeadChips for 90 samples including all NBS-participants who used HT within 5 y before surgery. Data were analyzed using the reference-free cell mixture method. Cancer Genome Atlas (TCGA) mRNA-Seq data were used to assess correlation between DNA methylation and gene expression. We identified 527 CpG sites in 403 genes that were associated with ever using HT at genome wide significance (FDR q < 0.05), of these, 68 sites were also significantly associated with duration of use or recency of use. Twelve sites reached significance in all analyses one of which was cg01382688 in ARHGEF4 (p < 1.2x10 −7). Mutations in ARHGEF4 have been reported in breast tumors, but this is the first report of possible breast cancer-related DNA methylation changes. In addition, 22 genes included more than one significant CpG site and a majority of these sites were significantly correlated with gene expression. Although based on small numbers, these findings support the hypothesis that HT is associated with epigenetic alterations in breast tissue, and identifies genes with altered DNA methylation states which could be linked to breast cancer development.

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“…Src homology 2 domain-containing protein 5 (SH2D5) is a mammalian-specific, uncharacterized adaptor-like protein that is highly enriched in brain at the transcriptional level (21). In the present study, we demonstrated that SH2D5 played an important role in the proliferation of HCC cells mediated by HBx.…”

mentioning

confidence: 64%

Hepatitis B virus X protein–induced SH2 domain–containing 5 (SH2D5) expression promotes hepatoma cell growth via an SH2D5–transketolase interaction

Yang

Ming

Zhu

et al. 2019

Journal of Biological Chemistry

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Src Homology 2 Domain Containing Protein 5 (SH2D5) Binds the Breakpoint Cluster Region Protein, BCR, and Regulates Levels of Rac1-GTP

Cited by 17 publications

References 30 publications

Mesenchymal stem cells promote endothelial progenitor cell migration, vascularization, and bone repair in tissue‐engineered constructs via activating CXCR2‐Src‐PKL/Vav2‐Rac1

Mesenchymal stem cells promote endothelial progenitor cell migration, vascularization, and bone repair in tissue‐engineered constructs via activating CXCR2‐Src‐PKL/Vav2‐Rac1

Hormone therapy use and breast tissue DNA methylation: analysis of epigenome wide data from the normal breast study

Hepatitis B virus X protein–induced SH2 domain–containing 5 (SH2D5) expression promotes hepatoma cell growth via an SH2D5–transketolase interaction

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